Exercise training and vascular remodelling in SHR
Hypertension is associated with vascular structural and mechanical changes including vascular remodelling and increased stiffness (Intengan and Schiffrin, 2000; Rizzoni and Agabiti-Rosei, 2012; Mulvany, 2012). The main feature of hypertensive vascular remodelling is an increase in the wall-to-lumen ratio, and this parameter has a prognostic value for cardiovascular events (Rizzoni et al., 2003; Mathiassen et al., 2007). In healthy subjects, exercise training induces structural vascular adaptations both in conductance and resistance coronary arteries (Laughlin et al., 2012). However, very little information is available on the effects of exercise on coronary and mesenteric resistance arteries of hypertensive patients and/or animal models of hypertension. Our results show that compared with WKY, both small mesenteric arteries and coronary arteries from SHR show eutrophic remodelling with unaltered cross-sectional area and increased wall-to-lumen ratio. Vessels from SHR also showed increased wall thickness that was due to increased adventitia and media thickness. This was associated with increased adventitial cells number in both arteries and with increased smooth muscle cells only in coronary arteries. In addition, SHR small mesenteric and coronary arteries display smaller incremental distensibility and enhanced vascular stiffness, which is consistent with previous studies performed mainly in mesenteric arteries (Mulvany, 1993; Intengan et al., 1999; Briones et al., 2003). Exercise training completely normalized the increased vascular stiffness and improved the decreased vascular distensibility observed at low pressure in small mesenteric and coronary arteries. Reduction of arterial stiffness by exercise training was observed in large arteries from hypertensive patients (Collier et al., 2008; Guimarães et al., 2010) and SHR (Hägg et al., 2004). However, to date, no studies have demonstrated the beneficial effects of exercise training in the increased vascular stiffness of coronary and mesenteric resistance arteries in hypertension. Of note, vascular stiffness is considered to be an indicator of subclinical organ damage in hypertension (Mancia et al., 2007). Exercise training did not modify the vascular remodelling observed in coronary arteries or mesenteric arteries from SHR. Improvement (Amaral et al., 2000; Melo et al., 2003; Rossoni et al., 2011) or no effects (Melo et al., 2003) of exercise training on vascular structure have been observed by other authors in other vascular beds from hypertensive animals. The questions of whether more prolonged or more intense training programmes or training started before the development of structural alterations would restore abnormal vessel structure remains as an attractive hypothesis that needs further consideration.
We previously demonstrated that in addition to collagen, elastin alterations are important determinants of small mesenteric arteries vascular stiffness (Briones et al., 2003). In fact, differences in elastin organisation particularly at the internal elastic lamina are central elements in small artery remodelling and increased stiffness in hypertension (Briones et al., 2003). Thus, there is a correlation between β-values (slope of the stress–strain relationship) and the area of fenestrae (González et al., 2005; 2006), demonstrating that the smaller the size of the fenestra the higher the stiffness of the vessel. Here, we observed that exercise training normalized the increased collagen deposition and improved the diminished fenestra size in the internal elastic lamina of small mesenteric arteries from SHR, providing an explanation of the beneficial effects of exercise in vascular stiffness and on vascular distensibility, particularly at low pressures, where elastin protein is operative. Recent studies performed in aorta from SHR also demonstrated that exercise training normalized alterations in the deposition of elastic components (Moraes-Teixeira et al., 2010; Jordão et al., 2011). Imbalance between the synthesis and degradation of ECM proteins might affect vascular stiffness. Our results demonstrate that exercise training differently affects expression of MMPs. Whereas exercise did not affect MMP-2 expression, it significantly normalized the decreased expression of the elastin degrading protein MMP-9, observed in the small mesenteric arteries from SHR.
Under pathological conditions, the production of ROS increases ECM proteins such as collagen and fibronectin (Briones and Touyz, 2010). In addition, we have previously demonstrated that in hypertension, the decrease of oxidative stress correlates with the normalization of the increased vascular stiffness, the altered internal elastic lamina structure and collagen deposition observed in small mesenteric arteries (Briones et al., 2009). Here, we have observed that exercise training decreased local oxidative stress (see below). Therefore, it is highly possible that there is a direct relationship between the improved NO–ROS status and the decreased vascular stiffness and alterations in ECM deposition observed after low intensity exercise.
Exercise training and vascular function in SHR
Endothelial dysfunction in hypertension is a multifactorial process resulting mainly from impaired NO availability due to a decrease in NO production and/or an increase in NO degradation associated to the increase of O2− production in this pathology (Briones and Touyz, 2010; Tang and Vanhoutte, 2010). The final consequence in general is increased contractile responses and/or decreased vasodilator responses.
The data presented here show that hypertension differently affects contractile responses in small mesenteric arteries and coronary arteries. The responses of coronary arteries to U46619, 5-HT and K+-KHS were lower in SHR than WKY, in agreement with other studies (Vazquez-Pérez et al., 2001), and suggest that contractile machinery and/or excitation-contraction coupling mechanisms may be impaired in the hypertensive coronary vasculature. In contrast, U46619-induced responses in mesenteric arteries were greater in SHR than WKY without changes to K+-KHS, as described previously (Beltrán et al., 2004). Interestingly, exercise training did not affect the altered contractile responses in SHR coronary arteries but it normalized the enhanced responses in mesenteric arteries.
Previous studies have demonstrated that aerobic exercise training of low intensity decreases oxidative stress in different tissues, including arteries of SHR by increasing the efficiency of the antioxidant system (Rush et al., 2003; Bertagnolli et al., 2008; Agarwal et al., 2009; 2012), thus increasing NO bioavailability (Hägg et al., 2004; Higashi and Yoshizumi, 2004). Our results further provide evidence that low intensity aerobic exercise of SHR decreases oxidative stress and increases NO bioavailability, allowing a complete reversal of the augmented contractile response observed in small mesenteric arteries. This is based on the following evidence: apocynin decreased U46619-induced contractile responses in SHR but not in WKY, and exercise training abolished this effect; O2− production was greater in SHR than WKY and exercise training abolished this increase; Cu/Zn SOD expression was decreased in SHR compared with WKY and exercise training also normalized this down-regulation; exercise training increased l-NAME effect on U46619-induced responses and vascular and plasma NO production.
Endothelium-dependent vasodilatation was impaired in coronary arteries from SHR, as previously described in coronary arteries from humans and hypertensive animal models (Crabos et al., 1997; Treasure et al., 1993; Vazquez-Pérez et al., 2001). Exercise training improved the impaired ACh vasodilatation by a mechanism dependent, at least in part, on the antioxidant effects of exercise. This is based on the fact that apocynin, which decreased O2− production in SHR, also improved the impaired ACh-induced relaxation in SHR but not in WKY, and exercise training abolished this effect. This is in agreement with other studies suggesting that regular physical activity was efficient in improving endothelial function of patients with coronary artery disease (Hambrecht et al., 2003) by improving NO bioavailability. However, to our knowledge, this is the first study demonstrating that the reduction of oxidative stress induced by exercise is responsible for the improvement in coronary artery endothelial dysfunction in hypertension. Other authors have demonstrated that exercise training also improves the participation of EDHF-dependent mechanisms in endothelium dependent relaxations (Gündüz et al., 2011; Yen et al., 1995).
Enhanced production of endothelium-derived contracting factors, such as prostanoids, can also antagonize relaxing actions and participate in endothelial dysfunction in hypertension (Félétou et al., 2011). Our results show that in phenylephrine-contracted SHR small mesenteric arteries, high concentrations of ACh induce endothelium-dependent contractions. This contractile response was abolished when the arteries were pre-contracted with U46619 instead of phenylephrine suggesting the involvement of TP receptors in this response. Importantly, this effect was attenuated in trained animals, suggesting that exercise might also affect the COX–TP receptor pathway. In support of this hypothesis, we also observed that exercise training normalized the increased U46619 responses in these arteries.
Aerobic training decreases blood pressure in hypertensive humans and animals (Bertagnolli et al., 2008; Agarwal et al., 2009; 2012; Lamina, 2010; Fernandes et al., 2012) mainly by reducing vascular resistance (Fagard and Cornelissen, 2007; Yung et al., 2009). In the present study, we observed that low intensity exercise attenuated the high blood pressure. This might be due, at least in part, to the beneficial effects observed here in the function, the mechanical properties and in the deposition of ECM proteins in the mesenteric and/or coronary vasculature. Alternatively, this haemodynamic effect of exercise training can contribute to the normalization of the altered properties of the arteries, and this poses the unresolved question of whether vascular abnormalities are a cause or a consequence of high blood pressure.
Here, we have observed that hypertension differently affected mesenteric and coronary arteries at the structural, mechanical and functional level. For example, coronary arteries from SHR showed a much higher increase in vascular stiffness than mesenteric arteries when compared with their normotensive controls. In addition, coronary arteries from SHR showed decreased vasoconstrictor induced responses to different stimuli, whereas hypertensive mesenteric arteries showed an increase or no alteration of these responses. It is possible that these differences might be related to the physiological roles of these vessels in the whole cardiovascular system. What is important is that independently of these differences, exercise training had a beneficial effect in both vascular beds pointing to the idea that these beneficial effects are not only limited to organs affected by exercise (muscle and heart mainly) but also to other peripheral organs that in the end can participate in blood pressure control.
In conclusion, the results presented here demonstrated that aerobic exercise training improved NO bioavailability and decreased the participation of ROS and prostanoids in vascular responses of coronary arteries and/or small mesenteric arteries from SHR. These changes contribute to the normalization of the altered vascular function by reducing contractile responses and by increasing endothelium-dependent relaxations. The reduction of oxidative stress might also beneficially modulate some of the structural and mechanical alterations such as collagen deposition and internal elastic lamina organization, which might be associated with the reduced vascular stiffness. All these beneficial changes in the resistance vasculature might partially decrease blood pressure and they also constitute strong evidence that low-intensity aerobic exercise is beneficial to the vascular system and could be considered as co-adjutant or as an alternative therapy, when appropriate, to pharmacological treatments for hypertension.