SEARCH

SEARCH BY CITATION

Keywords:

  • developmental programming;
  • endothelium;
  • microvasculature;
  • nutrition

Abstract

  1. Top of page
  2. Abstract
  3. Microvascular function
  4. Microvascular function in cardio-metabolic disease
  5. Vascular programming and later risk of cardiometabolic disease
  6. Mechanisms of microvascular programming
  7. Perspectives
  8. Conflict of interest
  9. References

There is compelling evidence that microvascular deficits affecting multiple tissues and organs play an important role in the aetiopathogenesis of cardio-metabolic disease. Furthermore, both in humans and animal models, deficits in small vessel structure and function can be detected early, often before the onset of macrovascular disease and the development of end-organ damage that is common to hypertension and obesity-associated clinical disorders. This article considers the growing evidence for the negative impact of an adverse maternal diet on the long-term health of her child, and how this can result in a disadvantageous vascular phenotype that extends to the microvascular bed. We describe how structural and functional modifications in the offspring microcirculation during development may represent an important and additional risk determinant to increase susceptibility to the development of cardio-metabolic disease in adult life and consider the cell-signalling pathways associated with endothelial dysfunction that may be ‘primed’ by the maternal environment. Published studies were identified that reported outcomes related to the microcirculation, endothelium, maternal diet and vascular programming using NCBI PubMed.gov, MEDLINE and ISI Web of Science databases from 1980 until April 2013 using pre-specified search terms. Information extracted from over 230 original reports and review articles was critically evaluated by the authors for inclusion in this review.

The metabolic syndrome is traditionally thought of as a non-communicable disease that occurs in adult life. It is characterized by at least three clinical risk factors which may include central obesity, hyperglycaemia, hyperinsulinaemia, raised serum triglyceride levels), low levels of high density lipoproteins and hypertension (Grundy et al. 2005). These risk factors predispose an increasing number of individuals to future type-2 diabetes mellitus and coronary heart disease, constituting one of the biggest health challenges in both developed and third-world countries today (Kassi et al. 2011, Defina et al. 2012). Epidemiological data from the National Health and Nutrition Examination Survey in the United States showed that the prevalence of metabolic syndrome (as defined by the National Cholesterol Education Program panel criteria) in adult males and females aged 20 years and over were 20.3 and 15.6%, respectively between 2003 and 2006 (Ervin 2009).

Various studies indicate that the aetiology of cardio-metabolic disease depends in part on the individual's genetic background as well as on lifestyle factors (smoking, high-calorie diets and inactivity). However, investigations into large-scale genome-wide associations have yet to provide strong evidence of a major genomic component such as single nucleotide repeats in the predisposition to the metabolic syndrome in the general population (Monda et al. 2010). Further, treatment strategies in the form of lifestyle interventions (diet and exercise) while often advised alongside pharmacological treatment have varied in their efficacy to reduce disease burden (Horton 2009). Mounting evidence now indicates that the rising incidence of cardio-metabolic disease may in fact have its origins in the individual's pre- and peri-natal environment (Gluckman et al. 2008). In the early 1990s, Hales and Barker reported that a strong risk factor for the development of cardio-metabolic disease was low birth weight (Hales & Barker 1992). Similarly, more recent evidence also demonstrates an inverse relationship between birth weight and cardiovascular disease and type-2 diabetes risk (Huxley et al. 2007, Whincup et al. 2008). Later insights led to the proposition that an altered maternal body composition and/or nutrition could give rise to permanent physiological and metabolic adaptations in the foetus and predispose it to the development of type-2 diabetes and metabolic syndrome in later life (Hales & Barker 2001, Armitage et al. 2008). Furthermore, it has been suggested that long-term effects of adaptations to an adverse intrauterine environment might be exacerbated if there is a nutritional mismatch between an individual's adaptations to the ‘predicted’ environment and the environment encountered in post-natal life (Gluckman et al. 2005).

For decades, investigations that targeted causal mechanisms of cardio-metabolic disorders neglected the likely involvement of a microvascular basis in their pathogenesis. Recent evidence suggests a link between microvascular dysfunction and cardio-metabolic disease and that structural and functional alteration in the microvasculature in key metabolic tissues and organs, resulting from exposure to an adverse maternal environment in early life, may constitute a key determinant in an individual's susceptibility to cardio-metabolic disease in adult life. This review focuses on our current understanding of the resultant magnitude and tissue-specific nature of these microvascular adaptations and current views of the functional outcomes of ‘developmental microvascular priming’ in early life.

Microvascular function

  1. Top of page
  2. Abstract
  3. Microvascular function
  4. Microvascular function in cardio-metabolic disease
  5. Vascular programming and later risk of cardiometabolic disease
  6. Mechanisms of microvascular programming
  7. Perspectives
  8. Conflict of interest
  9. References

The microvascular bed is generally taken to comprise small resistance arteries, arterioles, capillaries and venules with diameter <150 μm that lie within the tissue parenchyma (Pries & Secomb 2008). The fundamental structural variations between microvascular beds in different organs relate primarily to microvascular densities, branching patterns, and capillary ultrastructure, and the mechanisms by which vascular tone, and hence, tissue perfusion is regulated. The primary role of the microcirculation is to provide optimal exchange of gases, nutrients and metabolites between the blood and surrounding tissues. The physiological regulation of solute transfer is generally achieved through variations in the number of exchange vessels perfused and local blood flow. A reduction in either gives rise to suboptimal tissue perfusion and a failure to meet metabolic demand. Between 70 and 90% of the systemic arterial pressure may be delivered to the microcirculation. Thus, a second important role of the microvascular bed is to limit large fluctuations in hydrostatic pressure within the thin-walled capillaries. This is achieved at the level of arterioles through regulation of vascular tone, making the microvasculature an important site for the regulation of local and overall peripheral resistance and hence blood pressure (Delano et al. 1991).

Key to the regulation of vascular resistance and blood flow within the microvascular bed are local, neural and humoral and myogenic vasoregulatory mechanisms. Endothelial cells regulate vascular tone by releasing vasoconstrictors (e.g. thromboxane A2, endothelin-1, prostaglandin H2) and vasodilators that include nitric oxide (NO), prostacyclin (PGI2) and endothelium-derived hyperpolarization factors (EDHF; Feletou et al. 2010). The relative contribution of these mediators to maintain vascular tone and adequate tissue perfusion varies across the vascular tree, in many disease states and across the life course. For example, the contribution of EDHFs to vasodilator tone increases as vessel size decreases, with predominant EDHF activity in small resistance arteries and within the microvasculature (Potocnik et al. 2009, Edwards et al. 2010). In cardiovascular pathologies characterized by a reduced NO bioavailability, a compensatory up-regulation of EDHFs serves to sustain dilatation and maintain tissue perfusion (Feletou & Vanhoutte 2009, Giachini et al. 2009, Goto et al. 2012). Finally, in early post-natal life, the rapid enlargement of many organs is accompanied by extensive growth of their microvascular networks and tissue-specific alterations in metabolic requirements that necessitates changes in local blood flow regulation (Boegehold 2010). This maturational shift is associated with a change in the relative influence of vasoactive molecules that are organ-specific and includes NO, EDHFs and metabolites of cyclooxygenase (COX) (Boegehold 2010, Kang et al. 2012). Taken together, these observations provide evidence for considerable plasticity in microvascular control in early life.

Microvascular function in cardio-metabolic disease

  1. Top of page
  2. Abstract
  3. Microvascular function
  4. Microvascular function in cardio-metabolic disease
  5. Vascular programming and later risk of cardiometabolic disease
  6. Mechanisms of microvascular programming
  7. Perspectives
  8. Conflict of interest
  9. References

Evidence that disturbances in microvascular structure and function play a key role in the patho-physiological manifestations of cardio-metabolic disease comes from longitudinal and cross-sectional studies in human cohorts and from rodent models such as the obese Zucker rat (OZR), db/db and ob/ob mouse models of cardio-metabolic disease, for example (Jonk et al. 2007, De Boer et al. 2012). Microvascular dysfunction has been shown to be present in individuals with hypertension and type-2 diabetes as well as in overweight and obese individuals in the absence of insulin resistance and hypertension (Wiernsperger et al. 2007, De Boer et al. 2012). Blood flow in skeletal muscle and coronary microvascular beds has also been found to negatively correlate with insulin resistance, obesity and type 2 diabetes, both at rest and during increased metabolic demand (Bauer et al. 2007, Copp et al. 2010, Wu et al. 2011, Quercioli et al. 2012), and changes in capillary perfusion have been shown to influence skeletal muscle oxygen uptake and insulin-mediated glucose disposal (Clark 2008). Similarly, microvascular exchange surface area and perfusion have been shown to be negatively associated with central obesity, insulin resistance and features of the metabolic syndrome (Caton et al. 2009, Krentz et al. 2009, Clough et al. 2011).

Although it is widely accepted that changes in the microcirculation may occur before clinical manifestations of end-organ microvascular disease, the extent to which early changes in microvascular health and function impact on overall cardio-metabolic disease severity is still not fully understood. Furthermore, the magnitude and timing of the physical and functional remodelling of the peripheral vascular tree that occurs in cardio-metabolic diseases remain uncertain. As yet, few data are available on microvascular dysfunction in deep tissues, and the majority of studies that suggest a contributory role of the microcirculation to the development and progression of cardio-metabolic disease are largely confined to measurements in accessible vascular beds in humans such as the skin and retina and to those in animal models of cardio-metabolic disease.

Structural alterations of the microcirculation

Microvascular rarefaction, that is, altered microvessel numbers, branching patterns and microvessel morphology has been a consistent observation in obesity, hypertension and insulin-resistant states. These alterations result in constrained tissue/organ perfusion due to the longer capillary diffusion distances required for metabolic exchange (de Jongh et al. 2006, Levy et al. 2008). Studies using non-invasive vascular-imaging technologies suggest strong links between subtle changes in microcirculatory anatomy and both clinical and subclinical cardio-metabolic outcomes. In both the skin and retinal microcirculation, a reduction in capillary numbers and diameters has found in early stages of cardio-metabolic disease and worsen with the severity of disease (Sasongko et al. 2010, Benitez-Aguirre et al. 2011, Cheung et al. 2011, Gopinath et al. 2011, Ding et al. 2012, Sasongko et al. 2012). A direct relationship between insulin sensitivity and microvascular function has also been demonstrated, with endothelium-dependent vasodilatation and capillary recruitment in response to reactive hyperaemia inversely associated with insulin sensitivity in non-diabetic obese patients (Serne et al. 2002, de Jongh et al. 2004, Clough et al. 2009).

In db/db mice that represent a model of obesity, diabetes and dyslipidaemia, a reduction in network length and arteriolar lumen diameter is seen in the skeletal muscle microcirculation (Georgi et al. 2011). In the same report, the skeletal muscle of ob/ob mice, with hyperphagia, type-2 diabetes and obesity, displayed a significant alteration in microvascular network pattern and longer vessels with non-uniform lumen diameters (Georgi et al. 2011). Functional rarefaction in both db/db and ob/ob mice also gave rise to perfusion heterogeneity as a result of the reduction in the number of flow paths (Georgi et al. 2011). In non-obese diabetic rats, a significant reduction in capillary volume (Kondo et al. 2011), diameter and total microvascular surface area (Sexton et al. 1994) also appears indicative of structural rarefaction associated with vascular remodelling in the skeletal muscle microcirculation. Haemodynamic computational modelling studies using the spinotrapezius muscle from Zucker diabetic fatty rats showed a 37% decrease in microvascular branching and a 19% decrease in microvessel length density in early stages of the disease. Upon established diabetes in these rats, a 44% reduction in capillary network flow led to alterations in flow patterns as well as an insulin-mediated glucose exchange in skeletal muscles (Benedict et al. 2011). Similar findings have been reported from other animal studies and together suggest that microvascular rarefaction is associated with a decreased sensitivity and/or responsiveness to the metabolic actions of insulin and hence a reduced glucose disposal. In support of this, structural rarefaction in the microcirculation has been shown to lead to a marked insulin resistance in the skeletal muscle of the (lean) muscle-specific vascular endothelial growth factor (VEGF) knockout mouse (Bonner et al. 2012).

Interestingly, Frisbee (2005) has suggested that the reduction in skeletal muscle microvascular density in young OZRs, which exhibit a metabolic syndrome phenotype, was not associated with hypertension. This led them to suggest that in these rats, other factors associated with a metabolic syndrome phenotype, such as insulin resistance, may underlie the progression of microvascular rarefaction and the exacerbation of cardio-metabolic disease. Microvascular rarefaction has been implicated in the elevation of vascular resistance in other studies, including in a computer simulation model, where a reduction in functional capillary density beyond 30% led to an exponential increase in vascular resistance (Hudetz 1993).

A decreased microvascular density is also associated with increased flow heterogeneity in the microvascular bed, resulting in a non-uniform distribution of blood flow among exchange vessels. Accordingly, a mathematical model of the hamster cheek pouch microcirculation demonstrated that a 40% reduction in microvascular density was associated with a 20% increase vascular resistance and a profound heterogeneity of blood flow within the microcirculation (Greene et al. 1989). Altered flow distribution at the level of the microvascular network has also been shown to contribute to the failure of the microvessels to match skeletal muscle metabolic demand with perfusion (Turzyniecka et al. 2009, Frisbee et al. 2011, Wu et al. 2011). Hence, early microvascular rarefaction in cardio-metabolic disease may affect both pressure and flow patterns and have consequences not only for vascular resistance, but also for muscle perfusion and metabolism.

Functional alterations of microcirculation

Several lines of evidence indicate that mechanisms regulating vascular tone are altered in cardio-metabolic disease and that changes in endothelium-mediated vasoconstrictor and dilator responses mediated by locally produced autacoids contribute to microvascular dysfunction in such disease states (Tziomalos et al. 2010, Kabutoya et al. 2012, Rossi et al. 2013). The reduced availability of endogenous vasodilators required to maintain vascular tone and tissue perfusion has been attributed to the enhanced production of reactive oxygen species (ROS) in response to the elevated levels of pro-inflammatory cytokines, adipokines, glucose oxidation (in hyperglycaemic states) and free fatty acids (from peri-vascular adipose tissue; Goodwill & Frisbee 2012). Evidence for impaired endothelium-dependent NO-mediated dilation has been reported in numerous human studies in cardio-metabolic disease both in larger arteries using flow-mediated dilatation (FMD) and within the microvasculature using non-invasive imaging of the skin and deeper tissues (Steinberg et al. 1996, de Jongh et al. 2008, Kabutoya et al. 2012). Studies in rodent models have similarly shown alterations in NO-mediated dilation in skeletal muscle microcirculation (Frisbee 2003, 2005, Costa et al. 2011). The contribution of oxidative stress to these altered NO-mediated responses and microvascular dysfunction has been confirmed in cardio-metabolic disease (Pannirselvam et al. 2002, 2003, Cheang et al. 2011) and in the ageing microcirculation (Muller-Delp et al. 2012). Alterations in endothelium-dependent relaxation pathways due to oxidative stress have also been suggested to arise from reduced PGI2 levels as a result of altered arachidonic acid metabolism in the microcirculatory beds of skeletal muscle (Frisbee et al. 2009, Hodnett et al. 2009) and reproductive organs (Sanchez et al. 2010). Changes in non-NO-mediated vasodilation associated with the hyperpolarization of both endothelial and vascular smooth muscle cells have also been reported in diabetic, obese and insulin-resistant states with up-regulation of EDHF-mediated dilation in cardio-metabolic disease (Giachini et al. 2009, Vanhoutte et al. 2009).

In summary, studies in a variety of animal models and in human microvascular beds show there are many factors that may influence optimal tissue function and increase risk of cardio-metabolic disease. The finding of changes in capillary number and regulation of network perfusion and the evidence of plasticity within the microvascular bed across the life course collectively support the concept that the microvasculature may be a target for developmental ‘priming’ and that mal-adaptations in the structure and function of the microvasculature in key organs and tissues in early life may increase susceptibility to cardio-metabolic disease risk factors in adult life.

Vascular programming and later risk of cardiometabolic disease

  1. Top of page
  2. Abstract
  3. Microvascular function
  4. Microvascular function in cardio-metabolic disease
  5. Vascular programming and later risk of cardiometabolic disease
  6. Mechanisms of microvascular programming
  7. Perspectives
  8. Conflict of interest
  9. References

Deficits in vascular function, including at the level of the microvasculature, are strongly associated with birth weight (low and high) and later cardiovascular risk in infants, children and young adults born small or prematurely (Clough & Norman 2011, Torrens et al. 2011), and maternal calorific intake and calorific composition have been shown to influence microvascular angiogenesis, vasculogenesis and barrier integrity and maturation of the foetal vascular system (Leach 2011). In addition, a number of studies describe the effects of maternal diet and other maternal stressors on uterine and umbilical blood flows and the size of the placental vascular bed and their potential to affect foetal vascularization, independent of offspring birth weight so confirming the critical role of the placenta in developmental programming (Redmer et al. 2009, Meyer et al. 2010, Reynolds & Caton 2012). While there have been few investigations of associations between overnutrition/obesity in pregnant women and cardiovascular risk in their children, a positive association between gestational weight gain and offspring obesity and systolic blood pressure has been reported in young children (Lawlor et al. 2004, Oken 2009) and young adults, where a greater gestational weight gain was associated with greater BMI and systolic blood pressure (Mamun et al. 2009). There are also an increasing number of animal studies examining the association between maternal overnourishment/obesity, foetal growth rate and placental vascularity (Ma et al. 2010), foetal organ development (George et al. 2010) and offspring organ and vascular function and a cardio-metabolic disease phenotype (Taylor et al. 2004, Samuelsson et al. 2008, Bruce et al. 2009, Torrens et al. 2012, Dong et al. 2013) as reviewed by Ainge et al. (2011).

Maternal undernutrition

The first report linking ‘intrauterine under-nutrition’ with later obesity and cardiovascular disease was described in an epidemiological study on adult offspring of female survivors of the Dutch famine of 1944. Ravelli et al. (1976) suggested that maternal undernutrition during early gestation was associated with the development of hypertension in the offspring in adult life (Roseboom et al. 1999, 2001). In later stages of gestation, however, under-nutrition gave rise to offspring with an increased adiposity and glucose intolerance when subjects were compared to well-nourished offspring (Law et al. 1992, Ravelli et al. 1999). Studies in other human cohorts have shown similar findings. Yajnik et al. (1995, 2003) pioneered the first study of ‘foetal origins’ in India where they tested the hypothesis that low birth weight was an independent predictor of glucose tolerance and insulin resistance variables in 4- and 8-year-old urban children born in the city of Pune, India. Children with a low birth weight were found to have a significantly high systolic blood pressure, plasma cholesterol and insulin, and were significantly heavier than non-low-birth weight children. A more recent study showed that offspring born after the Chinese famine (1959–1961) had a higher risk of developing hyperglycaemia and type-2 diabetes in adulthood. This risk was found to be higher in subjects who went on to adopt a Western dietary pattern (Li et al. 2010). Together these studies also suggest that an important driver for future cardio-metabolic risk was the ‘nutritional mismatch’ experienced by the offspring during their intrauterine and early post-natal life. This paradigm formed the basis of the predictive adaptive response hypothesis described by Gluckman and colleagues (Gluckman & Hanson 2004, Gluckman et al. 2008, Vickers & Sloboda 2012).

Oxidative stress resulting from compromised endogenous antioxidant defences is a common feature of cardio-metabolic disease and has emerged as a key link between birth weight and increased morbidity later in life as a consequence of sustained oxidative stress. Reduced levels of superoxide dismutase, catalase, glutathione and serum malondialdehyde have been observed when cord blood from small for gestational age (SGA) babies was compared to that of healthy children that were born appropriate for gestational age (AGA) (Gupta et al. 2004). Furthermore, there is evidence that the raised levels of biomarkers of oxidative stress in addition to insulin resistance persist in pre-pubescent life (Franco et al. 2007, Chiavaroli et al. 2009).

Several human studies have also provided evidence for impaired endothelium-dependent and endothelium-independent vasodilation in low birth weight individuals at birth, at 3 months of age, in later childhood and in early adult life (Goh et al. 2001, Norman & Martin 2003). In infants, vascular dysfunction was evidenced by a significant reduction in acetylcholine-induced vasodilation in the microvasculature and a reduced ability of the brachial artery to dilate in response to increased blood flow following occlusion (Martin et al. 2000). In a recent study in children aged 7–15 year, it was observed that non-obese SGA children similarly displayed a lower FMD compared with obese AGA children (Jouret et al. 2011).

In many countries, preterm birth is a more common cause of low birth weight than foetal growth restriction. Prematurely born infants display an increased risk for developing metabolic (insulin resistance) and cardiovascular disorders (elevated blood pressure and abnormal retinal vasculature) as adults (Kistner et al. 2005, Kerkhof et al. 2012). Interestingly, these individuals have been shown to have otherwise healthy endothelial function in childhood and early adulthood at both microvascular and macrovascular levels (Bonamy et al. 2005, 2007, Mikkola et al. 2007). Adolescents and young adults born premature have higher blood pressure, abnormal retinal vascularization and lower peripheral skin blood flow than control subjects (Kistner et al. 2002, Bonamy et al. 2005). In another study, adult women born preterm appear to have a 2.5-fold increased risk of developing hypertension compared with women born at term (Pouta et al. 2004). Interestingly, in those studies, SGA subjects were not different from AGA subjects, both within the premature and the term groups, suggesting an important role of preterm birth itself in the programming of cardiovascular function in later life. Although the mechanisms linking prematurity and later cardiovascular disorders remain unclear, it is evident that it is associated with impaired nephrogenesis and vasculogenesis (Gilbert et al. 2005, 2007) as well as oxidative stress (Yeung 2006), all of which may contribute to later end-organ microvascular dysfunction and the risk of developing cardio-metabolic disease. The extent to which the microvasculature is altered in other tissues in premature and low birth weight individuals has important implications for cardio-metabolic health, and remains to be clarified. For instance, muscle capillary density determines diffusion and tissue concentration of insulin, as described above. Functional and/or structural loss of muscle capillaries could therefore be a mechanism linking low birth weight and/or preterm birth to later insulin resistance.

Intrauterine undernutrition is associated with endothelial vasodilator dysfunction in the adult offspring (Lamireau et al. 2002, Taylor et al. 2004, Torrens et al. 2009). Animal models of maternal undernutrition support a role for programming of hypertension through altered endothelium-dependent dilations in resistance arteries in the offspring (Torrens et al. 2003) via altered NO signalling (Rodford et al. 2008, Torrens et al. 2009). Consistent with this, Lamireau et al. (2002) showed that maternal protein deprivation resulted in a 50% reduction of NO-dependent relaxation in resistance cerebral microvessels which was associated with reduced cGMP and soluble guanylate cyclase expression. Reduced NO levels in undernourished offspring have also been attributed to oxidative stress following an increased superoxide generation (Ceravolo et al. 2007) and reduced tetrahydrobiopterin (BH4), an important cofactor in nitric oxide synthase (NOS) activity and therefore in the conversion of L-Arg to NO, in resistance arteries (Franco et al. 2002, 2003, 2004). The administration of antioxidants (Franco et al. 2003) and exogenous BH4 (Franco et al. 2004) was found to reduce oxidative stress and blood pressure thus improving vascular function. In support of this, endothelial dysfunction and reduced antioxidant protection in resistance arteries in male offspring of protein-restricted rats were linked to the reduced expression of the antioxidant enzyme, haem oxygenase-1 (HO-1) (Rodford et al. 2008).

Strong correlations between endothelial function in adult offspring and micronutrient intake during pregnancy have also been found. In a protein-restricted model, low folate levels were linked to a reduced NO bioavailability and endothelial NOS mRNA expression (Torrens et al. 2006). Similarly, vitamin D deficiency during development and early life in rats was associated with a reduced EDHF-induced dilation and an increased myogenic tone in resistance arteries in adult offspring (Tare et al. 2011).

Structural alterations in small resistance arteries have also been implicated in mediating vascular dysfunction and hypertension in offspring exposed to intrauterine calorie restriction (Khorram et al. 2007a,2007a,2007c). For example, reduced microvessel numbers and branches found in the mesenteric and renal microcirculation as a result of decreased angiogenesis in offspring of calorie restricted dams are thought to contribute to an increased peripheral vascular resistance and hypertension in later life (Khorram et al. 2007c). Further, capillary rarefaction in skeletal muscle in young rats (7 and 28 days old) but not in foetal rats with programmed raised blood pressure associated with a maternal low-protein diet, suggesting an early post-natal disruption in normal microvascular development (Pladys et al. 2005). In the sheep, capillary rarefaction in skeletal muscle and a reduced capillary to myofibre ratio have also been linked to a reduction in myofibre density but not in size, in a muscle-specific manner, following maternal undernutrition (Costello et al. 2008).

Microvascular rarefaction associated with impaired angiogenesis or active disappearance of blood vessels has been reported in some but not in all maternal dietary restriction models in skeletal muscle and cerebral cortex (Pladys et al. 2005, Khorram et al. 2007a, Costello et al. 2008) and reviewed by Clough and Norman (2011). A reduced NO bioactivity or increased oxidative stress in early life that is associated with many dietary models could be postulated to impact on microvessel formation and survival through perturbation of angiogenic and/or apoptosis signalling pathways (Pladys et al. 2005, Cambonie et al. 2007, Neville et al. 2010). However, a reduction in VEGF and VEGFR protein expression seen in neonates appears reversed and/or normalized by adulthood (Khorram et al. 2007b). Placental IGF-I synthesis is also down-regulated in placental insufficiency and foetal growth restriction, and low serum concentrations of IGF-I in preterm infants have been associated with growth arrest of the microvasculature in the eye (Hellstrom et al. 2003) which is modifiable by nutritional intervention (Engstrom et al. 2005).

An imbalance between angiogenic and anti-angiogenic factors involved in regulation of number and function of foetal endothelial progenitor cells has also been suggested to be involved in developmental programming of hypertension and cardiovascular disease (Ligi et al. 2010). Altered angiogenic properties of cord blood endothelial colony-forming cells (ECFCs) have been in preterm neonates compared with those studied at term (Ligi et al. 2011). Similarly, subsets of circulating progenitor cells (CPCs) with robust angiogenesis-facilitating functions have been shown to be reduced in women with gestational diabetes (Acosta et al. 2011). However, the impact of these increases in CPCs does not appear to be translated into altered vascular function in the neonates, as endothelial function appears normal (Acosta et al. 2011). Thus, to what extent impaired angiogenic properties of CPCs and ECFCs and other factors may influence early vascular remodelling and/or angiogenesis has yet to be explored.

Nutrient restriction has also been shown to induce remodelling of the vascular extracellular matrix with increased collagen deposition and matrix metalloproteinase expression in the walls of both mesenteric arterioles and the aorta, perhaps driven by the overexpression of VEGF, in adult offspring (Khorram et al. 2007a). Other studies report a 30% reduction in venular basement membrane type IV collagen in 8-week-old male offspring of undernourished rat dams (Landgraf et al. 2007) which may also modify angiogenesis and/or apoptosis of microvessels. More recently, maternal undernutrition has been shown to alter offspring vascular expression of micro-RNAs (miRNAs) including those targeting genes involved with the regulation of collagen, elastin, enzymes involved in ECM remodelling and angiogenic factors (Khorram et al. 2010,). These in turn could regulate the expression of genes involved with angiogenesis and extracellular matrix remodelling. While these findings help us to understand the links between the early life environment and structural remodelling of the microvasculature, the cell-signalling mechanisms that underlie functional deficits have yet to be fully elucidated.

Animal studies also give insight into the effects of the timing of dietary intervention in pregnancy on the extent of vascular programming. Intrauterine growth restriction in late gestation led to region-specific programming of vascular dysfunction, but not to hypertension and obesity in 18-month-old female offspring. In these females, vascular dysfunction, as manifested by a reduction in EDHF-mediated relaxation and structural rarefaction, was seen in the uterine artery but not in the mesenteric, renal and femoral arteries (Mazzuca et al. 2010). In contrast, intrauterine growth restriction induced by restricting blood flow to the gravid uterus (day 14 of gestation) in rats resulted in growth-restricted female offspring that were hypertensive as adults and had an increased smooth muscle contractility and altered endothelium-dependent and -independent relaxation in the mesenteric microcirculation (Anderson et al. 2006). Further, the effects on the offspring were transgenerational. More recently, Torrens and others showed the vascular effects of foetal programming may have long-term consequences for the development of the next generation of offspring. In this study, offspring of rats that experienced intrauterine protein restriction exhibited a high blood pressure and endothelial dysfunction even in the absence of an additional dietary challenge (Torrens et al. 2008).

Maternal overnutrition

Consistent with the developmental origins of cardiovascular disease hypothesis, altered vascular biology is not confined to those who are small at birth. Epidemiological data from human cohorts have shown a positive correlation between increased birth weight (used as a surrogate for maternal overnutrition) and a high BMI and/or obesity in adulthood (Sen et al. 2012). In addition to weight gain, other studies have provided a strong link between maternal obesity and subsequent development of the metabolic syndrome in adulthood, independent of maternal diabetes (Boney et al. 2005). However, while an association between maternal overnutrition and foetal growth, adiposity and cardiovascular risk factors in well-nourished populations (Drake & Reynolds 2010, Freeman 2010) has been shown, there is little evidence as yet for the consequences of maternal overnutrition on offspring microvascular function. However, the maternal insulin resistance, which is induced by an increased maternal fat mass, is likely to affect not only foetal growth, but also microvascular structure and function. Increased maternal body fat, serum leptin and triglycerides are associated with altered placental vascular development and a 30% decrease in the number of mature blood vessels that stained positive for smooth muscle actin (Hayes et al. 2012) which these authors hypothesize may result in a reduced oxygenation of foetal tissue contributing to poorer outcomes. A number of recent studies have further shown that greater pre-pregnancy BMI and pregnancy BMI are associated with adverse retinal microvessel number and structure (Li et al. 2012) and that retinal arterioles and venules may be differentially associated with offspring growth in early life, and early adiposity may adversely affect the microcirculation (Tapp et al. 2013).

In a recent systematic review by Ainge et al. (2011) of studies on developmentally primed offspring of overnourished rodent dams, including ad libitum feeding of high-fat diets supplemented with sweetened condensed milk or high-fat and/or high sugar junk food/cafeteria diet who are then weaned onto a laboratory chow diet, offspring consistently exhibited hyperphagia, increased adiposity, hypertension, abnormal glucose homoeostasis and reduced insulin sensitivity, and endothelial dysfunction in resistance and conduit arteries that persists into adulthood (Samuelsson et al. 2008, Elahi et al. 2009). Furthermore, there is increasing evidence that these cardio-metabolic disease risk factors persist in spite of a healthier post-natal diet (Taylor et al. 2004, Armitage et al. 2008) and may be increased further by an adverse post-weaning diet and by age (Ford & Long 2011, Masuyama & Hiramatsu 2012, Torrens et al. 2012, Yan et al. 2013). Similarly, we (Torrens et al. 2012) have shown there to be significant effects of maternal diet on offspring body weight, systolic blood pressure and endothelium-dependent relaxation to ACh measured in the femoral artery. Having controlled for differences in maternal diet, post-weaning offspring diet significantly influenced systolic blood pressure and endothelium-dependent relaxation. There was also a significant interaction between maternal diet and offspring diet to influence NO bioavailability associated with an increase in ROS in the artery wall and insulin resistance (Bruce et al. 2009). In humans, an increased expression of ROS in the placenta has been suggested to be one of the initiating factors in neonatal insulin resistance and obesity in response to maternal overnutrition (Radaelli et al. 2003).

While the NO pathway has been implicated in the endothelial dysfunction observed in the offspring of overnourished mothers, this does not apply to all models or all arteries. In their model of maternal high fat, Khan et al. (2005) showed impaired dilatation of the mesenteric arteries to ACh, which was still present after blockade of NOS and COX pathways, leading them to suggest this was an EDHF-related adaptation. Interestingly, this did not appear to be the case in the femoral arteries of the same animals. Evidence for an up-regulation of EDHF-mediated relaxation is seen in small resistance arteries and arterioles from other animal models of diet-induced obesity (Chadha et al. 2010, Feher et al. 2010, Haddock et al. 2011), hypercholesterolaemia (Ashraf et al. 2007), hypertension (Zhang et al. 2011), diabetes (Leo et al. 2011) and in apolipoprotein E and low density lipoprotein receptor-deficient mice fed a high-fat diet in adult life (Wolfle et al. 2009). Further, Kelsall et al. (2012) have demonstrated that in addition to an altered ACh-mediated vasorelaxation in mesenteric arteries from offspring of high-fat-fed rat dams, the type and amount of maternal dietary fat differentially influenced vasomotor tone and de novo biosynthesis of arachidonic acid in vascular smooth muscle. The extent to which the foetal environment impacts on EDHF or other signalling pathways in the human microcirculation remains to be established. Further, the impact of low-grade inflammation in the maternal environment through increased expression of pro-inflammatory cytokine genes and ROS in the placenta (Radaelli et al. 2003, Zhu et al. 2010), and increased foetal serum levels of TNF-α and IL-6 (Stewart et al. 2007) on the microvasculature has yet to be elucidated.

Mechanisms of microvascular programming

  1. Top of page
  2. Abstract
  3. Microvascular function
  4. Microvascular function in cardio-metabolic disease
  5. Vascular programming and later risk of cardiometabolic disease
  6. Mechanisms of microvascular programming
  7. Perspectives
  8. Conflict of interest
  9. References

The aim of this review was to explore the evidence for the impact of the maternal environment on microvessel structure and function in the offspring and the influence that this might have on later risk of cardio-metabolic disease. Through this it has become clear that programmed microvascular structural and functional rarefaction are associated with a complex range of causal and/or contributing factors but that the mechanisms underlying a ‘primed’ microvasculature remain obscure. Epigenetic dysregulation has been reported to mediate a number of the effects of early nutritional status on adult cardio-metabolic phenotype (Langley-Evans 2013). Thus, while many studies support that there are transgenerational effects of maternal under and overnutrition on the microvasculature, evidence for changes in DNA methylation or methylCpG-binding domain proteins at the level of the microvasculature or in microvascular microRNAs (Zhang et al. 2009) has yet to emerge. We can only speculate that changes in the microvascular epigenome may contribute to microvascular priming.

Perspectives

  1. Top of page
  2. Abstract
  3. Microvascular function
  4. Microvascular function in cardio-metabolic disease
  5. Vascular programming and later risk of cardiometabolic disease
  6. Mechanisms of microvascular programming
  7. Perspectives
  8. Conflict of interest
  9. References

It is currently estimated that over 20% of women of childbearing age and almost 25% of pregnant women in the UK are overweight or obese with a BMI >30 kg m−2. Higher maternal weight entering pregnancy is associated with higher weight and consequent risk for obesity, elevated blood pressure and diabetes among children. Obesity, hypertension and impaired insulin-mediated glucose disposal are all associated with abnormal microvascular structure and function. In the short term, elucidation of the impact of the developmental environment on the microvasculature, and of how structural or functional rarefaction during development limits the functional capacity of the microvasculature, will provide a much needed scientific basis for future mechanistic studies into programmed deficits in microvascular function in key tissues and organs.

Microvascular (dys)function is easily and non-invasively measured in a clinical setting. Subclinical changes in the microvasculature resulting from unfavourable lifestyle and environmental factors may therefore be detected early and possibly reversed through lifestyle interventions such as diet and exercise that are associated with reduced risk of microvascular disease. In the longer term, the identification of ‘primed’ proteins and genes associated with microvascular signalling pathways and the mechanisms by which this priming occurs may inform targeted intervention studies in at risk women and their children to improve microvascular function before the onset of overt cardiovascular and metabolic disease.

References

  1. Top of page
  2. Abstract
  3. Microvascular function
  4. Microvascular function in cardio-metabolic disease
  5. Vascular programming and later risk of cardiometabolic disease
  6. Mechanisms of microvascular programming
  7. Perspectives
  8. Conflict of interest
  9. References
  • Acosta, J.C., Haas, D.M., Saha, C.K., Dimeglio, L.A., Ingram, D.A. & Haneline, L.S. 2011. Gestational diabetes mellitus alters maternal and neonatal circulating endothelial progenitor cell subsets. Am J Obstet Gynecol 204, 254.e8254.e15.
  • Ainge, H., Thompson, C., Ozanne, S.E. & Rooney, K.B. 2011. A systematic review on animal models of maternal high fat feeding and offspring glycaemic control. Int J Obes (Lond) 35, 325335.
  • Anderson, C.M., Lopez, F., Zimmer, A. & Benoit, J.N. 2006. Placental insufficiency leads to developmental hypertension and mesenteric artery dysfunction in two generations of Sprague–Dawley rat offspring. Biol Reprod 74, 538544.
  • Armitage, J.A., Poston, L. & Taylor, P.D. 2008. Developmental origins of obesity and the metabolic syndrome: the role of maternal obesity. Front Horm Res 36, 7384.
  • Ashraf, M.Z., Reddy, M.K., Hussain, M.E., Podrez, E.A. & Fahim, M. 2007. Contribution of EDRF and EDHF to restoration of endothelial function following dietary restrictions in hypercholesterolemic rats. Indian J Exp Biol 45, 505514.
  • Bauer, T.A., Reusch, J.E., Levi, M. & Regensteiner, J.G. 2007. Skeletal muscle deoxygenation after the onset of moderate exercise suggests slowed microvascular blood flow kinetics in type 2 diabetes. Diabetes Care 30, 28802885.
  • Benedict, K.F., Coffin, G.S., Barrett, E.J. & Skalak, T.C. 2011. Hemodynamic systems analysis of capillary network remodeling during the progression of type 2 diabetes. Microcirculation 18, 6373.
  • Benitez-Aguirre, P., Craig, M.E., Sasongko, M.B., Jenkins, A.J., Wong, T.Y., Wang, J.J., Cheung, N. & Donaghue, K.C. 2011. Retinal vascular geometry predicts incident retinopathy in young people with type 1 diabetes: a prospective cohort study from adolescence. Diabetes Care 34, 16221627.
  • Boegehold, M.A. 2010. Endothelium-dependent control of vascular tone during early postnatal and juvenile growth. Microcirculation 17, 394406.
  • Bonamy, A.K., Bendito, A., Martin, H., Andolf, E., Sedin, G. & Norman, M. 2005. Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls. Pediatr Res 58, 845849.
  • Bonamy, A.K., Martin, H., Jorneskog, G. & Norman, M. 2007. Lower skin capillary density, normal endothelial function and higher blood pressure in children born preterm. J Intern Med 262, 635642.
  • Boney, C.M., Verma, A., Tucker, R. & Vohr, B.R. 2005. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics 115, e290e296.
  • Bonner, J.S., Lantier, L., Hasenour, C.M., James, F.D., Bracy, D.P. & Wasserman, D.H. 2012. Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance. Diabetes 62, 572580.
  • Bruce, K.D., Cagampang, F.R., Argenton, M., Zhang, J., Ethirajan, P.L., Burdge, G.C., Bateman, A.C., Clough, G.F., Poston, L., Hanson, M.A., McConnell, J.M. & Byrne, C.D. 2009. Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression. Hepatology 50, 17961808.
  • Cambonie, G., Comte, B., Yzydorczyk, C., Ntimbane, T., Germain, N., Le, N.L., Pladys, P., Gauthier, C., Lahaie, I., Abran, D., Lavoie, J.C. & Nuyt, A.M. 2007. Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet. Am J Physiol Regul Integr Comp Physiol 292, R1236R1245.
  • Caton, J.S., Reed, J.J., Aitken, R.P., Milne, J.S., Borowicz, P.P., Reynolds, L.P., Redmer, D.A. & Wallace, J.M. 2009. Effects of maternal nutrition and stage of gestation on body weight, visceral organ mass, and indices of jejunal cellularity, proliferation, and vascularity in pregnant ewe lambs. J Anim Sci 87, 222235.
  • Ceravolo, G.S., Franco, M.C., Carneiro-Ramos, M.S., Barreto-Chaves, M.L., Tostes, R.C., Nigro, D., Fortes, Z.B. & Carvalho, M.H. 2007. Enalapril and losartan restored blood pressure and vascular reactivity in intrauterine undernourished rats. Life Sci 80, 782787.
  • Chadha, P.S., Haddock, R.E., Howitt, L., Morris, M.J., Murphy, T.V., Grayson, T.H. & Sandow, S.L. 2010. Obesity up-regulates intermediate conductance calcium-activated potassium channels and myoendothelial gap junctions to maintain endothelial vasodilator function. J Pharmacol Exp Ther 335, 284293.
  • Cheang, W.S., Wong, W.T., Tian, X.Y., Yang, Q., Lee, H.K., He, G.W., Yao, X. & Huang, Y. 2011. Endothelial nitric oxide synthase enhancer reduces oxidative stress and restores endothelial function in db/db mice. Cardiovasc Res 92, 267275.
  • Cheung, C.Y., Zheng, Y., Hsu, W., Lee, M.L., Lau, Q.P., Mitchell, P., Wang, J.J., Klein, R. & Wong, T.Y. 2011. Retinal vascular tortuosity, blood pressure, and cardiovascular risk factors. Ophthalmology 118, 812818.
  • Chiavaroli, V., Giannini, C., D'Adamo, E., de, G.T., Chiarelli, F. & Mohn, A. 2009. Insulin resistance and oxidative stress in children born small and large for gestational age. Pediatrics 124, 695702.
  • Clark, M.G. 2008. Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscle. Am J Physiol Endocrinol Metab 295, E732E750.
  • Clough, G.F. & Norman, M. 2011. The microcirculation: a target for developmental priming. Microcirculation 18, 286297.
  • Clough, G.F., Turzyniecka, M., Walter, L., Krentz, A.J., Wild, S.H., Chipperfield, A.J., Gamble, J. & Byrne, C.D. 2009. Muscle microvascular dysfunction in central obesity is related to muscle insulin insensitivity but is not reversed by high-dose statin treatment. Diabetes 58, 11851191.
  • Clough, G.F., L'Esperance, V., Turzyniecka, M., Walter, L., Chipperfield, A.J., Gamble, J., Krentz, A.J. & Byrne, C.D. 2011. Functional dilator capacity is independently associated with insulin sensitivity and age in central obesity and is not improved by high dose statin treatment. Microcirculation 18, 7484.
  • Copp, S.W., Hageman, K.S., Behnke, B.J., Poole, D.C. & Musch, T.I. 2010. Effects of type II diabetes on exercising skeletal muscle blood flow in the rat. J Appl Physiol 109, 13471353.
  • Costa, R.R., Villela, N.R., Souza, M.G., Boa, B.C., Cyrino, F.Z., Silva, S.V., Lisboa, P.C., Moura, E.G., Barja-Fidalgo, T.C. & Bouskela, E. 2011. High fat diet induces central obesity, insulin resistance and microvascular dysfunction in hamsters. Microvasc Res 82, 416422.
  • Costello, P.M., Rowlerson, A., Astaman, N.A., Anthony, F.E., Sayer, A.A., Cooper, C., Hanson, M.A. & Green, L.R. 2008. Peri-implantation and late gestation maternal undernutrition differentially affect fetal sheep skeletal muscle development. J Physiol 586, 23712379.
  • De Boer, M.P., Meijer, R.I., Wijnstok, N.J., Jonk, A.M., Houben, A.J., Stehouwer, C.D., Smulders, Y.M., Eringa, E.C. & Serne, E.H. 2012. Microvascular dysfunction: a potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension. Microcirculation 19, 518.
  • Defina, L.F., Vega, G.L., Leonard, D. & Grundy, S.M. 2012. Fasting glucose, obesity, and metabolic syndrome as predictors of type 2 diabetes: the cooper center longitudinal study. J Investig Med 60, 11641168.
  • Delano, F.A., Schmid-Schonbein, G.W., Skalak, T.C. & Zweifach, B.W. 1991. Penetration of the systemic blood pressure into the microvasculature of rat skeletal muscle. Microvasc Res 41, 92110.
  • Ding, J., Cheung, C.Y., Ikram, M.K., Zheng, Y.F., Cheng, C.Y., Lamoureux, E.L., Tai, E.S., Subramaniam, T. & Wong, T.Y. 2012. Early retinal arteriolar changes and peripheral neuropathy in diabetes. Diabetes Care 35, 10981104.
  • Dong, M., Zheng, Q., Ford, S.P., Nathanielsz, P.W. & Ren, J. 2013. Maternal obesity, lipotoxicity and cardiovascular diseases in offspring. J Mol Cell Cardiol 55, 111116.
  • Drake, A.J. & Reynolds, R.M. 2010. Impact of maternal obesity on offspring obesity and cardiometabolic disease risk. Reproduction 140, 387398.
  • Edwards, G., Feletou, M. & Weston, A.H. 2010. Endothelium-derived hyperpolarising factors and associated pathways: a synopsis. Pflugers Arch 459, 863879.
  • Elahi, M.M., Cagampang, F.R., Mukhtar, D., Anthony, F.W., Ohri, S.K. & Hanson, M.A. 2009. Long-term maternal high-fat feeding from weaning through pregnancy and lactation predisposes offspring to hypertension, raised plasma lipids and fatty liver in mice. Br J Nutr 102, 514519.
  • Engstrom, E., Niklasson, A., Wikland, K.A., Ewald, U. & Hellstrom, A. 2005. The role of maternal factors, postnatal nutrition, weight gain, and gender in regulation of serum IGF-I among preterm infants. Pediatr Res 57, 605610.
  • Ervin, R.B. 2009. Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 2003–2006. Natl Health Stat Report 5, 17.
  • Feher, A., Rutkai, I., Beleznai, T., Ungvari, Z., Csiszar, A., Edes, I. & Bagi, Z. 2010. Caveolin-1 limits the contribution of BK(Ca) channel to EDHF-mediated arteriolar dilation: implications in diet-induced obesity. Cardiovasc Res 87, 732739.
  • Feletou, M. & Vanhoutte, P.M. 2009. EDHF: an update. Clin Sci (Lond) 117, 139155.
  • Feletou, M., Huang, Y. & Vanhoutte, P.M. 2010. Vasoconstrictor prostanoids. Pflugers Arch 459, 941950.
  • Ford, S.P. & Long, N.M. 2011. Evidence for similar changes in offspring phenotype following either maternal undernutrition or overnutrition: potential impact on fetal epigenetic mechanisms. Reprod Fertil Dev 24, 105111.
  • Franco, M.C., Dantas, A.P., Akamine, E.H., Kawamoto, E.M., Fortes, Z.B., Scavone, C., Tostes, R.C., Carvalho, M.H. & Nigro, D. 2002. Enhanced oxidative stress as a potential mechanism underlying the programming of hypertension in utero. J Cardiovasc Pharmacol 40, 501509.
  • Franco, M.C., Akamine, E.H., Di Marco, G.S., Casarini, D.E., Fortes, Z.B., Tostes, R.C., Carvalho, M.H. & Nigro, D. 2003. NADPH oxidase and enhanced superoxide generation in intrauterine undernourished rats: involvement of the renin-angiotensin system. Cardiovasc Res 59, 767775.
  • Franco, M.C., Fortes, Z.B., Akamine, E.H., Kawamoto, E.M., Scavone, C., de Britto, L.R., Muscara, M.N., Teixeira, S.A., Tostes, R.C., Carvalho, M.H. & Nigro, D. 2004. Tetrahydrobiopterin improves endothelial dysfunction and vascular oxidative stress in microvessels of intrauterine undernourished rats. J Physiol 558, 239248.
  • Franco, M.C., Akamine, E.H., Reboucas, N., Carvalho, M.H., Tostes, R.C., Nigro, D. & Fortes, Z.B. 2007. Long-term effects of intrauterine malnutrition on vascular function in female offspring: implications of oxidative stress. Life Sci 80, 709715.
  • Freeman, D.J. 2010. Effects of maternal obesity on fetal growth and body composition: implications for programming and future health. Semin Fetal Neonatal Med 15, 113118.
  • Frisbee, J.C. 2003. Remodeling of the skeletal muscle microcirculation increases resistance to perfusion in obese Zucker rats. Am J Physiol Heart Circ Physiol 285, H104H111.
  • Frisbee, J.C. 2005. Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 289, R307R316.
  • Frisbee, J.C., Hollander, J.M., Brock, R.W., Yu, H.G. & Boegehold, M.A. 2009. Integration of skeletal muscle resistance arteriolar reactivity for perfusion responses in the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 296, R1771R1782.
  • Frisbee, J.C., Wu, F., Goodwill, A.G., Butcher, J.T. & Beard, D.A. 2011. Spatial heterogeneity in skeletal muscle microvascular blood flow distribution is increased in the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 301, R975R986.
  • George, L.A., Uthlaut, A.B., Long, N.M., Zhang, L., Ma, Y., Smith, D.T., Nathanielsz, P.W. & Ford, S.P. 2010. Different levels of overnutrition and weight gain during pregnancy have differential effects on fetal growth and organ development. Reprod Biol Endocrinol 8, 75.
  • Georgi, M.K., Vigilance, J., Dewar, A.M. & Frame, M.D. 2011. Terminal arteriolar network structure/function and plasma cytokine levels in db/db and ob/ob mouse skeletal muscle. Microcirculation 18, 238251.
  • Giachini, F.R., Carneiro, F.S., Lima, V.V., Carneiro, Z.N., Dorrance, A., Webb, R.C. & Tostes, R.C. 2009. Upregulation of intermediate calcium-activated potassium channels counterbalance the impaired endothelium-dependent vasodilation in stroke-prone spontaneously hypertensive rats. Transl Res 154, 183193.
  • Gilbert, J.S., Lang, A.L., Grant, A.R. & Nijland, M.J. 2005. Maternal nutrient restriction in sheep: hypertension and decreased nephron number in offspring at 9 months of age. J Physiol 565, 137147.
  • Gilbert, J.S., Ford, S.P., Lang, A.L., Pahl, L.R., Drumhiller, M.C., Babcock, S.A., Nathanielsz, P.W. & Nijland, M.J. 2007. Nutrient restriction impairs nephrogenesis in a gender-specific manner in the ovine fetus. Pediatr Res 61, 4247.
  • Gluckman, P.D. & Hanson, M.A. 2004. The developmental origins of the metabolic syndrome. Trends Endocrinol Metab 15, 183187.
  • Gluckman, P.D., Cutfield, W., Hofman, P. & Hanson, M.A. 2005. The fetal, neonatal, and infant environments-the long-term consequences for disease risk. Early Hum Dev 81, 5159.
  • Gluckman, P.D., Hanson, M.A., Cooper, C. & Thornburg, K.L. 2008. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359, 6173.
  • Goh, K.L., Shore, A.C., Quinn, M. & Tooke, J.E. 2001. Impaired microvascular vasodilatory function in 3-month-old infants of low birth weight. Diabetes Care 24, 11021107.
  • Goodwill, A.G. & Frisbee, J.C. 2012. Oxidant stress and skeletal muscle microvasculopathy in the metabolic syndrome. Vascul Pharmacol 57, 150159.
  • Gopinath, B., Baur, L.A., Teber, E., Liew, G., Wong, T.Y. & Mitchell, P. 2011. Effect of obesity on retinal vascular structure in pre-adolescent children. Int J Pediatr Obes 6, e353e359.
  • Goto, K., Kansui, Y., Oniki, H., Ohtsubo, T., Matsumura, K. & Kitazono, T. 2012. Upregulation of endothelium-derived hyperpolarizing factor compensates for the loss of nitric oxide in mesenteric arteries of Dahl salt-sensitive hypertensive rats. Hypertens Res 35, 849854.
  • Greene, A.S., Tonellato, P.J., Lui, J., Lombard, J.H. & Cowley, A.W. Jr 1989. Microvascular rarefaction and tissue vascular resistance in hypertension. Am J Physiol 256, H126H131.
  • Grundy, S.M., Cleeman, J.I., Daniels, S.R., Donato, K.A., Eckel, R.H., Franklin, B.A., Gordon, D.J., Krauss, R.M., Savage, P.J., Smith, S.C. Jr, Spertus, J.A. & Costa, F. 2005. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112, 27352752.
  • Gupta, P., Narang, M., Banerjee, B.D. & Basu, S. 2004. Oxidative stress in term small for gestational age neonates born to undernourished mothers: a case control study. BMC Pediatr 4, 14.
  • Haddock, R.E., Grayson, T.H., Morris, M.J., Howitt, L., Chadha, P.S. & Sandow, S.L. 2011. Diet-induced obesity impairs endothelium-derived hyperpolarization via altered potassium channel signaling mechanisms. PLoS One 6, e16423.
  • Hales, C.N. & Barker, D.J. 1992. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35, 595601.
  • Hales, C.N. & Barker, D.J. 2001. The thrifty phenotype hypothesis. Br Med Bull 60, 520.
  • Hayes, E.K., Lechowicz, A., Petrik, J.J., Storozhuk, Y., Paez-Parent, S., Dai, Q., Samjoo, I.A., Mansell, M., Gruslin, A., Holloway, A.C. & Raha, S. 2012. Adverse fetal and neonatal outcomes associated with a life-long high fat diet: role of altered development of the placental vasculature. PLoS One 7, e33370.
  • Hellstrom, A., Engstrom, E., Hard, A.L., Albertsson-Wikland, K., Carlsson, B., Niklasson, A., Lofqvist, C., Svensson, E., Holm, S., Ewald, U., Holmstrom, G. & Smith, L.E. 2003. Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pediatrics 112, 10161020.
  • Hodnett, B.L., Dearman, J.A., Carter, C.B. & Hester, R.L. 2009. Attenuated PGI2 synthesis in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol 296, R715R721.
  • Horton, E.S. 2009. Effects of lifestyle changes to reduce risks of diabetes and associated cardiovascular risks: results from large scale efficacy trials. Obesity (Silver Spring) 17(Suppl 3), S43S48.
  • Hudetz, A.G. 1993. Percolation phenomenon: the effect of capillary network rarefaction. Microvasc Res 45, 110.
  • Huxley, R., Barzi, F., Lee, C.M., Lear, S., Shaw, J., Lam, T.H., Caterson, I., Azizi, F., Patel, J., Suriyawongpaisal, P. et al. 2007. Waist circumference thresholds provide an accurate and widely applicable method for the discrimination of diabetes. Diabetes Care 30, 31163118.
  • de Jongh, R.T., Serne, E.H., IJzerman, R.G., de, V.G. & Stehouwer, C.D. 2004. Impaired microvascular function in obesity: implications for obesity-associated microangiopathy, hypertension, and insulin resistance. Circulation 109, 25292535.
  • de Jongh, R.T., IJzerman, R.G., Serne, E.H., Voordouw, J.J., Yudkin, J.S., de Waal, H.A., Stehouwer, C.D. & van Weissenbruch, M.M. 2006. Visceral and truncal subcutaneous adipose tissue are associated with impaired capillary recruitment in healthy individuals. J Clin Endocrinol Metab 91, 51005106.
  • de Jongh, R.T., Serne, E.H., IJzerman, R.G., Jorstad, H.T. & Stehouwer, C.D. 2008. Impaired local microvascular vasodilatory effects of insulin and reduced skin microvascular vasomotion in obese women. Microvasc Res 75, 256262.
  • Jonk, A.M., Houben, A.J., de Jongh, R.T., Serne, E.H., Schaper, N.C. & Stehouwer, C.D. 2007. Microvascular dysfunction in obesity: a potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension. Physiology (Bethesda) 22, 252260.
  • Jouret, B., Dulac, Y., Bassil, E.R., Taktak, A., Cristini, C., Lounis, N., Molinas, C., Salles, J.P., Arnaud, C., Acar, P. & Tauber, M. 2011. Endothelial function and mechanical arterial properties in children born small for gestational age: comparison with obese children. Horm Res Paediatr 76, 240247.
  • Kabutoya, T., Hoshide, S., Ogata, Y., Iwata, T., Eguchi, K. & Kario, K. 2012. The time course of flow-mediated vasodilation and endothelial dysfunction in patients with a cardiovascular risk factor. J Am Soc Hypertens 6, 109116.
  • Kang, L.S., Nurkiewicz, T.R., Wu, G. & Boegehold, M.A. 2012. Changes in eNOS phosphorylation contribute to increased arteriolar NO release during juvenile growth. Am J Physiol Heart Circ Physiol 302, H560H566.
  • Kassi, E., Pervanidou, P., Kaltsas, G. & Chrousos, G. 2011. Metabolic syndrome: definitions and controversies. BMC Med 9, 48.
  • Kelsall, C.J., Hoile, S.P., Irvine, N.A., Masoodi, M., Torrens, C., Lillycrop, K.A., Calder, P.C., Clough, G.F., Hanson, M.A. & Burdge, G.C. 2012. Vascular dysfunction induced in offspring by maternal dietary fat involves altered arterial polyunsaturated fatty acid biosynthesis. PLoS One 7, e34492.
  • Kerkhof, G.F., Breukhoven, P.E., Leunissen, R.W., Willemsen, R.H. & Hokken-Koelega, A.C. 2012. Does preterm birth influence cardiovascular risk in early adulthood? J Pediatr 161, 390396.
  • Khan, I.Y., Dekou, V., Douglas, G., Jensen, R., Hanson, M.A., Poston, L. & Taylor, P.D. 2005. A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring. Am J Physiol Regul Integr Comp Physiol 288, R127R133.
  • Khorram, O., Khorram, N., Momeni, M., Han, G., Halem, J., Desai, M. & Ross, M.G. 2007a. Maternal undernutrition inhibits angiogenesis in the offspring: a potential mechanism of programmed hypertension. Am J Physiol Regul Integr Comp Physiol 293, R745R753.
  • Khorram, O., Momeni, M., Desai, M. & Ross, M.G. 2007b. Nutrient restriction in utero induces remodeling of the vascular extracellular matrix in rat offspring. Reprod Sci 14, 7380.
  • Khorram, O., Momeni, M., Ferrini, M., Desai, M. & Ross, M.G. 2007c. In utero undernutrition in rats induces increased vascular smooth muscle content in the offspring. Am J Obstet Gynecol 196, 486488.
  • Khorram, O., Han, G., Bagherpour, R., Magee, T.R., Desai, M., Ross, M.G., Chaudhri, A.A., Toloubeydokhti, T. & Pearce, W.J. 2010. Effect of maternal undernutrition on vascular expression of micro and messenger RNA in newborn and aging offspring. Am J Physiol Regul Integr Comp Physiol 298, R1366R1374.
  • Kistner, A., Jacobson, L., Jacobson, S.H., Svensson, E. & Hellstrom, A. 2002. Low gestational age associated with abnormal retinal vascularization and increased blood pressure in adult women. Pediatr Res 51, 675680.
  • Kistner, A., Celsi, G., Vanpee, M. & Jacobson, S.H. 2005. Increased systolic daily ambulatory blood pressure in adult women born preterm. Pediatr Nephrol 20, 232233.
  • Kondo, T., Osugi, S., Shimokata, K., Honjo, H., Morita, Y., Yamashita, K., Maeda, K., Muramatsu, T., Shintani, S., Matsushita, K. & Murohara, T. 2011. Metabolic syndrome and all-cause mortality, cardiac events, and cardiovascular events: a follow-up study in 25,471 young- and middle-aged Japanese men. Eur J Cardiovasc Prev Rehabil 18, 574580.
  • Krentz, A.J., Clough, G. & Byrne, C.D. 2009. Vascular disease in the metabolic syndrome: do we need to target the microcirculation to treat large vessel disease? J Vasc Res 46, 515526.
  • Lamireau, D., Nuyt, A.M., Hou, X., Bernier, S., Beauchamp, M., Gobeil, F. Jr, Lahaie, I., Varma, D.R. & Chemtob, S. 2002. Altered vascular function in fetal programming of hypertension. Stroke 33, 29922998.
  • Landgraf, M.A., Tostes, R.C., Borelli, P., Zorn, T.M., Nigro, D., Carvalho, M.H. & Fortes, Z.B. 2007. Mechanisms involved in the reduced leukocyte migration in intrauterine undernourishment. Nutrition 23, 145156.
  • Langley-Evans, S.C. 2013. Fetal programming of CVD and renal disease: animal models and mechanistic considerations. Proc Nutr Soc 14, 19.
  • Law, C.M., Barker, D.J., Osmond, C., Fall, C.H. & Simmonds, S.J. 1992. Early growth and abdominal fatness in adult life. J Epidemiol Community Health 46, 184186.
  • Lawlor, D.A., Najman, J.M., Sterne, J., Williams, G.M., Ebrahim, S. & Davey, S.G. 2004. Associations of parental, birth, and early life characteristics with systolic blood pressure at 5 years of age: findings from the Mater-University study of pregnancy and its outcomes. Circulation 110, 24172423.
  • Leach, L. 2011. Placental vascular dysfunction in diabetic pregnancies: intimations of fetal cardiovascular disease? Microcirculation 18, 263269.
  • Leo, C.H., Hart, J.L. & Woodman, O.L. 2011. Impairment of both nitric oxide-mediated and EDHF-type relaxation in small mesenteric arteries from rats with streptozotocin-induced diabetes. Br J Pharmacol 162, 365377.
  • Levy, B.I., Schiffrin, E.L., Mourad, J.J., Agostini, D., Vicaut, E., Safar, M.E. & Struijker-Boudier, H.A. 2008. Impaired tissue perfusion: a pathology common to hypertension, obesity, and diabetes mellitus. Circulation 118, 968976.
  • Li, J.B., Wang, X., Zhang, J.X., Gu, P., Zhang, X., Chen, C.X., Guo, R. & Wu, M. 2010. Metabolic syndrome: prevalence and risk factors in southern China. J Int Med Res 38, 11421148.
  • Li, L.J., Ikram, M.K., Cheung, C.Y., Lee, Y.S., Lee, L.J., Gluckman, P., Godfrey, K.M., Chong, Y.S., Kwek, K., Wong, T.Y. & Saw, S.M. 2012. Effect of maternal body mass index on the retinal microvasculature in pregnancy. Obstet Gynecol 120, 627635.
  • Ligi, I., Grandvuillemin, I., Andres, V., Dignat-George, F. & Simeoni, U. 2010. Low birth weight infants and the developmental programming of hypertension: a focus on vascular factors. Semin Perinatol 34, 188192.
  • Ligi, I., Simoncini, S., Tellier, E., Vassallo, P.F., Sabatier, F., Guillet, B., Lamy, E., Sarlon, G., Quemener, C., Bikfalvi, A. et al. 2011. A switch toward angiostatic gene expression impairs the angiogenic properties of endothelial progenitor cells in low birth weight preterm infants. Blood 118, 16991709.
  • Ma, Y., Zhu, M.J., Zhang, L., Hein, S.M., Nathanielsz, P.W. & Ford, S.P. 2010. Maternal obesity and overnutrition alter fetal growth rate and cotyledonary vascularity and angiogenic factor expression in the ewe. Am J Physiol Regul Integr Comp Physiol 299, R249R258.
  • Mamun, A.A., O'Callaghan, M., Callaway, L., Williams, G., Najman, J. & Lawlor, D.A. 2009. Associations of gestational weight gain with offspring body mass index and blood pressure at 21 years of age: evidence from a birth cohort study. Circulation 119, 17201727.
  • Martin, H., Gazelius, B. & Norman, M. 2000. Impaired acetylcholine-induced vascular relaxation in low birth weight infants: implications for adult hypertension? Pediatr Res 47, 457462.
  • Masuyama, H. & Hiramatsu, Y. 2012. Effects of a high-fat diet exposure in utero on the metabolic syndrome-like phenomenon in mouse offspring through epigenetic changes in adipocytokine gene expression. Endocrinology 153, 28232830.
  • Mazzuca, M.Q., Wlodek, M.E., Dragomir, N.M., Parkington, H.C. & Tare, M. 2010. Uteroplacental insufficiency programs regional vascular dysfunction and alters arterial stiffness in female offspring. J Physiol 588, 19972010.
  • Meyer, A.M., Reed, J.J., Vonnahme, K.A., Soto-Navarro, S.A., Reynolds, L.P., Ford, S.P., Hess, B.W. & Caton, J.S. 2010. Effects of stage of gestation and nutrient restriction during early to mid-gestation on maternal and fetal visceral organ mass and indices of jejunal growth and vascularity in beef cows. J Anim Sci 88, 24102424.
  • Mikkola, K., Leipala, J., Boldt, T. & Fellman, V. 2007. Fetal growth restriction in preterm infants and cardiovascular function at five years of age. J Pediatr 151(494–9), 499.
  • Monda, K.L., North, K.E., Hunt, S.C., Rao, D.C., Province, M.A. & Kraja, A.T. 2010. The genetics of obesity and the metabolic syndrome. Endocr Metab Immune Disord Drug Targets 10, 86108.
  • Muller-Delp, J.M., Gurovich, A.N., Christou, D.D. & Leeuwenburgh, C. 2012. Redox balance in the aging microcirculation: new friends, new foes, and new clinical directions. Microcirculation 19, 1928.
  • Neville, T.L., Redmer, D.A., Borowicz, P.P., Reed, J.J., Ward, M.A., Johnson, M.L., Taylor, J.B., Soto-Navarro, S.A., Vonnahme, K.A., Reynolds, L.P. & Caton, J.S. 2010. Maternal dietary restriction and selenium supply alters mRNA expression of angiogenic factors in maternal intestine, mammary gland, and fetal jejunal tissues during late gestation in pregnant ewe lambs. J Anim Sci 88, 26922702.
  • Norman, M. & Martin, H. 2003. Preterm birth attenuates association between low birth weight and endothelial dysfunction. Circulation 108, 9961001.
  • Oken, E. 2009. Maternal and child obesity: the causal link. Obstet Gynecol Clin North Am 36, 361377.
  • Pannirselvam, M., Verma, S., Anderson, T.J. & Triggle, C.R. 2002. Cellular basis of endothelial dysfunction in small mesenteric arteries from spontaneously diabetic (db/db −/−) mice: role of decreased tetrahydrobiopterin bioavailability. Br J Pharmacol 136, 255263.
  • Pannirselvam, M., Simon, V., Verma, S., Anderson, T. & Triggle, C.R. 2003. Chronic oral supplementation with sepiapterin prevents endothelial dysfunction and oxidative stress in small mesenteric arteries from diabetic (db/db) mice. Br J Pharmacol 140, 701706.
  • Pladys, P., Sennlaub, F., Brault, S., Checchin, D., Lahaie, I., Le, N.L., Bibeau, K., Cambonie, G., Abran, D., Brochu, M., Thibault, G., Hardy, P., Chemtob, S. & Nuyt, A.M. 2005. Microvascular rarefaction and decreased angiogenesis in rats with fetal programming of hypertension associated with exposure to a low-protein diet in utero. Am J Physiol Regul Integr Comp Physiol 289, R1580R1588.
  • Potocnik, S.J., McSherry, I., Ding, H., Murphy, T.V., Kotecha, N., Dora, K.A., Yuill, K.H., Triggle, C.R. & Hill, M.A. 2009. Endothelium-dependent vasodilation in myogenically active mouse skeletal muscle arterioles: role of EDH and K(+) channels. Microcirculation 16, 377390.
  • Pouta, A., Hartikainen, A.L., Sovio, U., Gissler, M., Laitinen, J., McCarthy, M.I., Ruokonen, A., Elliott, P. & Jarvelin, M.R. 2004. Manifestations of metabolic syndrome after hypertensive pregnancy. Hypertension 43, 825831.
  • Pries, A.R. & Secomb, T.W. 2008. Modeling structural adaptation of microcirculation. Microcirculation 15, 753764.
  • Quercioli, A., Pataky, Z., Montecucco, F., Carballo, S., Thomas, A., Staub, C., Di Marzo, V., Vincenti, G., Ambrosio, G., Ratib, O., Golay, A., Mach, F., Harsch, E. & Schindler, T.H. 2012. Coronary vasomotor control in obesity and morbid obesity: contrasting flow responses with endocannabinoids, leptin, and inflammation. JACC Cardiovasc Imaging 5, 805815.
  • Radaelli, T., Varastehpour, A., Catalano, P. & Hauguel-De, M.S. 2003. Gestational diabetes induces placental genes for chronic stress and inflammatory pathways. Diabetes 52, 29512958.
  • Ravelli, G.P., Stein, Z.A. & Susser, M.W. 1976. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 295, 349353.
  • Ravelli, A.C., Van Der Meulen, J.H., Osmond, C., Barker, D.J. & Bleker, O.P. 1999. Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 70, 811816.
  • Redmer, D.A., Luther, J.S., Milne, J.S., Aitken, R.P., Johnson, M.L., Borowicz, P.P., Borowicz, M.A., Reynolds, L.P. & Wallace, J.M. 2009. Fetoplacental growth and vascular development in overnourished adolescent sheep at day 50, 90 and 130 of gestation. Reproduction 137, 749757.
  • Reynolds, L.P. & Caton, J.S. 2012. Role of the pre- and post-natal environment in developmental programming of health and productivity. Mol Cell Endocrinol 354, 5459.
  • Rodford, J.L., Torrens, C., Siow, R.C., Mann, G.E., Hanson, M.A. & Clough, G.F. 2008. Endothelial dysfunction and reduced antioxidant protection in an animal model of the developmental origins of cardiovascular disease. J Physiol 586, 47094720.
  • Roseboom, T.J., Van Der Meulen, J.H., Ravelli, A.C., van Montfrans, G.A., Osmond, C., Barker, D.J. & Bleker, O.P. 1999. Blood pressure in adults after prenatal exposure to famine. J Hypertens 17, 325330.
  • Roseboom, T.J., Van Der Meulen, J.H., Ravelli, A.C., Osmond, C., Barker, D.J. & Bleker, O.P. 2001. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Mol Cell Endocrinol 185, 9398.
  • Rossi, A.M., Davies, E., Lavoie, K.L., Arsenault, A., Gordon, J.L., Meloche, B. & Bacon, S.L. 2013. The impact of metabolic syndrome and endothelial dysfunction on exercise-induced cardiovascular changes. Obesity (Silver Spring) 21, E143E148.
  • Samuelsson, A.M., Matthews, P.A., Argenton, M., Christie, M.R., McConnell, J.M., Jansen, E.H., Piersma, A.H., Ozanne, S.E., Twinn, D.F., Remacle, C., Rowlerson, A., Poston, L. & Taylor, P.D. 2008. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension 51, 383392.
  • Sanchez, A., Contreras, C., Villalba, N., Martinez, P., Martinez, A.C., Briones, A., Salaices, M., Garcia-Sacristan, A., Hernandez, M. & Prieto, D. 2010. Altered arachidonic acid metabolism via COX-1 and COX-2 contributes to the endothelial dysfunction of penile arteries from obese Zucker rats. Br J Pharmacol 159, 604616.
  • Sasongko, M.B., Wong, T.Y. & Wang, J.J. 2010. Retinal arteriolar changes: intermediate pathways linking early life exposures to cardiovascular disease? Microcirculation 17, 2131.
  • Sasongko, M.B., Wong, T.Y., Nguyen, T.T., Shaw, J.E., Jenkins, A.J. & Wang, J.J. 2012. Novel versus traditional risk markers for diabetic retinopathy. Diabetologia 55, 666670.
  • Sen, S., Carpenter, A.H., Hochstadt, J., Huddleston, J.Y., Kustanovich, V., Reynolds, A.A. & Roberts, S. 2012. Nutrition, weight gain and eating behavior in pregnancy: a review of experimental evidence for long-term effects on the risk of obesity in offspring. Physiol Behav 107, 138145.
  • Serne, E.H., IJzerman, R.G., Gans, R.O., Nijveldt, R., de, V.G., Evertz, R., Donker, A.J. & Stehouwer, C.D. 2002. Direct evidence for insulin-induced capillary recruitment in skin of healthy subjects during physiological hyperinsulinemia. Diabetes 51, 15151522.
  • Sexton, W.L., Poole, D.C. & Mathieu-Costello, O. 1994. Microcirculatory structure–function relationships in skeletal muscle of diabetic rats. Am J Physiol 266, H1502H1511.
  • Steinberg, H.O., Chaker, H., Leaming, R., Johnson, A., Brechtel, G. & Baron, A.D. 1996. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 97, 26012610.
  • Stewart, F.M., Freeman, D.J., Ramsay, J.E., Greer, I.A., Caslake, M. & Ferrell, W.R. 2007. Longitudinal assessment of maternal endothelial function and markers of inflammation and placental function throughout pregnancy in lean and obese mothers. J Clin Endocrinol Metab 92, 969975.
  • Tapp, R.J., Ness, A., Williams, C., Howe, L.D., Tilling, K., Witt, N., Chaturvedi, N., McG Thom, S.A. & Hughes, A.D. 2013. Differential effects of adiposity and childhood growth trajectories on retinal microvascular architecture. Microcirculation 21; doi: 10.1111/micc.12060. [Epub ahead of print].
  • Tare, M., Emmett, S.J., Coleman, H.A., Skordilis, C., Eyles, D.W., Morley, R. & Parkington, H.C. 2011. Vitamin D insufficiency is associated with impaired vascular endothelial and smooth muscle function and hypertension in young rats. J Physiol 589, 47774786.
  • Taylor, P.D., Khan, I.Y., Hanson, M.A. & Poston, L. 2004. Impaired EDHF-mediated vasodilatation in adult offspring of rats exposed to a fat-rich diet in pregnancy. J Physiol 558, 943951.
  • Torrens, C., Brawley, L., Barker, A.C., Itoh, S., Poston, L. & Hanson, M.A. 2003. Maternal protein restriction in the rat impairs resistance artery but not conduit artery function in pregnant offspring. J Physiol 547, 7784.
  • Torrens, C., Brawley, L., Anthony, F.W., Dance, C.S., Dunn, R., Jackson, A.A., Poston, L. & Hanson, M.A. 2006. Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction. Hypertension 47, 982987.
  • Torrens, C., Poston, L. & Hanson, M.A. 2008. Transmission of raised blood pressure and endothelial dysfunction to the F2 generation induced by maternal protein restriction in the F0, in the absence of dietary challenge in the F1 generation. Br J Nutr 100, 760766.
  • Torrens, C., Hanson, M.A., Gluckman, P.D. & Vickers, M.H. 2009. Maternal undernutrition leads to endothelial dysfunction in adult male rat offspring independent of postnatal diet. Br J Nutr 101, 2733.
  • Torrens, C., Clough, G.F. & Hanson, M.A. 2011. Developmental origins of endothelial dysfunction: a key step in cardiometabolic disease. In: C.D. Byrne & S.H. Wild (eds) The Metabolic Syndrome, pp. 4559. Wiley-Blackwell, Oxford.
  • Torrens, C., Ethirajan, P., Bruce, K.D., Cagampang, F.R., Siow, R.C., Hanson, M.A., Byrne, C.D., Mann, G.E. & Clough, G.F. 2012. Interaction between maternal and offspring diet to impair vascular function and oxidative balance in high fat fed male mice. PLoS One 7, e50671.
  • Turzyniecka, M., Wild, S.H., Krentz, A.J., Chipperfield, A.J., Gamble, J., Clough, G.F. & Byrne, C.D. 2009. Skeletal muscle microvascular exchange capacity is associated with hyperglycaemia in subjects with central obesity. Diabet Med 26, 11121119.
  • Tziomalos, K., Athyros, V.G., Karagiannis, A. & Mikhailidis, D.P. 2010. Endothelial dysfunction in metabolic syndrome: prevalence, pathogenesis and management. Nutr Metab Cardiovasc Dis 20, 140146.
  • Vanhoutte, P.M., Shimokawa, H., Tang, E.H. & Feletou, M. 2009. Endothelial dysfunction and vascular disease. Acta Physiol (Oxf) 196, 193222.
  • Vickers, M.H. & Sloboda, D.M. 2012. Strategies for reversing the effects of metabolic disorders induced as a consequence of developmental programming. Front Physiol 3, 242.
  • Whincup, P.H., Kaye, S.J., Owen, C.G., Huxley, R., Cook, D.G., Anazawa, S., Barrett-Connor, E., Bhargava, S.K., Birgisdottir, B.E., Carlsson, S. et al. 2008. Birth weight and risk of type 2 diabetes: a systematic review. JAMA 300, 28862897.
  • Wiernsperger, N., Nivoit, P., De Aguiar, L.G. & Bouskela, E. 2007. Microcirculation and the metabolic syndrome. Microcirculation 14, 403438.
  • Wolfle, S.E., Schmidt, V.J., Hoyer, J., Kohler, R. & de, W.C. 2009. Prominent role of KCa3.1 in endothelium-derived hyperpolarizing factor-type dilations and conducted responses in the microcirculation in vivo. Cardiovasc Res 82, 476483.
  • Wu, F., Beard, D.A. & Frisbee, J.C. 2011. Computational analyses of intravascular tracer washout reveal altered capillary-level flow distributions in obese Zucker rats. J Physiol 589, 45274543.
  • Yajnik, C.S., Fall, C.H., Vaidya, U., Pandit, A.N., Bavdekar, A., Bhat, D.S., Osmond, C., Hales, C.N. & Barker, D.J. 1995. Fetal growth and glucose and insulin metabolism in four-year-old Indian children. Diabet Med 12, 330336.
  • Yajnik, C.S., Fall, C.H., Coyaji, K.J., Hirve, S.S., Rao, S., Barker, D.J., Joglekar, C. & Kellingray, S. 2003. Neonatal anthropometry: the thin-fat Indian baby. The Pune Maternal Nutrition Study. Int J Obes Relat Metab Disord 27, 173180.
  • Yan, X., Huang, Y., Zhao, J.X., Rogers, C.J., Zhu, M.J., Ford, S.P., Nathanielsz, P.W. & Du, M. 2013. Maternal obesity downregulates microRNA let-7 g expression, a possible mechanism for enhanced adipogenesis during ovine fetal skeletal muscle development. Int J Obes (Lond) 37, 568575.
  • Yeung, M.Y. 2006. Postnatal growth, neurodevelopment and altered adiposity after preterm birth–from a clinical nutrition perspective. Acta Paediatr 95, 909917.
  • Zhang, J., Zhang, F., Didelot, X., Bruce, K.D., Cagampang, F.R., Vatish, M., Hanson, M., Lehnert, H., Ceriello, A. & Byrne, C.D. 2009. Maternal high fat diet during pregnancy and lactation alters hepatic expression of insulin like growth factor-2 and key microRNAs in the adult offspring. BMC Genomics 10, 478.
  • Zhang, L.N., Vincelette, J., Chen, D., Gless, R.D., Anandan, S.K., Rubanyi, G.M., Webb, H.K., MacIntyre, D.E. & Wang, Y.X. 2011. Inhibition of soluble epoxide hydrolase attenuates endothelial dysfunction in animal models of diabetes, obesity and hypertension. Eur J Pharmacol 654, 6874.
  • Zhu, M.J., Du, M., Nathanielsz, P.W. & Ford, S.P. 2010. Maternal obesity up-regulates inflammatory signaling pathways and enhances cytokine expression in the mid-gestation sheep placenta. Placenta 31, 387391.