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Keywords:

  • portal hypertension;
  • hepatic stellate cells;
  • hepatic sinusoid

Abstract

  1. Top of page
  2. Abstract
  3. PORTAL HYPERTENSION
  4. CONTRACTILE CELLS WHICH COULD BE INVOLVED IN PORTAL HYPERTENSION
  5. CONTRACTILE APPARATUS OF HSC
  6. MECHANISMS OF HSC CONTRACTION AND RELAXATION
  7. WHICH SUBSTANCES INDUCE CONTRACTION/RELAXATION OF HSC?
  8. CONCLUSIONS
  9. LITERATURE CITED

Portal hypertension, a major complication of cirrhosis, is caused by both increased portal blood flow and augmented intrahepatic vascular resistance. Even though the latter is primarily caused by anatomical changes, it has become clear that dynamic factors contribute to the increased hepatic vascular resistance. The hepatic sinusoid is the narrowest vascular structure within the liver and is the principal site of blood flow regulation. The anatomical location of hepatic stellate cells, which embrace the sinusoids, provides a favorable arrangement for sinusoidal constriction, and for control of sinusoidal vascular tone and blood flow. Hepatic stellate cells possess the essential contractile apparatus for cell contraction and relaxation. Moreover, the mechanisms of stellate cell contraction are better understood, and many substances which influence contractility have been identified, providing a rationale and opportunity for targeting these cells in the treatment of portal hypertension in cirrhosis. Anat Rec, 291:693–698, 2008. © 2008 Wiley-Liss, Inc.

The liver is a richly perfused organ: Although the liver represents only 2.5% of body weight, it receives approximately 25% of the cardiac output by means of a dual blood supply. Approximately 75% of blood enters the liver through the portal vein, the remainder by means of the hepatic artery. Nutrient rich portal venous blood drains in the sinusoids, whereas oxygen rich arterial blood enters the sinusoids at different sites. Thus, mixed arterial and venous blood passes through the liver sinusoids.

In normal liver, vascular resistance is very low thereby keeping portal pressure low. Portal hypertension occurs in the setting of augmented portal blood flow and increased vascular resistance. Increased vascular resistance can occur at different locations: prehepatic (e.g., portal vein obstruction), posthepatic (e.g., hepatic vein obstruction) as well as intrahepatic (cirrhosis; Gupta et al.,1997; Laleman et al.,2005). In this review, we will only discuss portal hypertension caused by intrahepatic disturbances in the context of cirrhosis. Portal hypertension is responsible for several potentially lethal complications of cirrhosis, including the development of esophago-gastric varices, ascites, hepato-renal syndrome, hepato-pulmonary syndrome and porto-systemic encephalopathy. Over the past decades, our knowledge of the pathophysiology of portal hypertension has greatly increased, which now provides a rational approach to new treatment options. It is clear that both intra- and extrahepatic blood flow are abnormal in cirrhotic subjects with portal hypertension. Morphological aspects, extrahepatic blood flow and blood flow regulation in normal liver are discussed elsewhere in this issue. In this review, we will summarize data on sinusoidal blood flow regulation in portal hypertension and possible treatment options.

PORTAL HYPERTENSION

  1. Top of page
  2. Abstract
  3. PORTAL HYPERTENSION
  4. CONTRACTILE CELLS WHICH COULD BE INVOLVED IN PORTAL HYPERTENSION
  5. CONTRACTILE APPARATUS OF HSC
  6. MECHANISMS OF HSC CONTRACTION AND RELAXATION
  7. WHICH SUBSTANCES INDUCE CONTRACTION/RELAXATION OF HSC?
  8. CONCLUSIONS
  9. LITERATURE CITED

As in any vascular system, portal venous pressure is proportional to blood flow scular resistance. According to Ohm's law (ΔP = Q × R), the change in portal pressure along a vessel (ΔP) equals the product of the portal blood flow (Q) and the resistance to flow (R; Gupta et al.,1997). In normal liver, the intrahepatic resistance changes with variations in hepatic blood flow, thereby keeping portal pressure within normal limits. In cirrhosis however, both intrahepatic vascular resistance and portal blood flow are increased. These two events disturb the equilibrium in the system and trigger portal hypertension. The initial event in the pathophysiology of portal hypertension is augmented vascular resistance to portal blood flow. Increased blood flow in the portal vein, caused by the hyperdynamic circulation in the splanchnic blood vessels, occurs at a more advanced stage of portal hypertension and contributes to its persistence and aggravation.

Increased intrahepatic vascular resistance is primarily caused by anatomical changes such as fibrotic scar tissue and regenerative nodules compressing portal and central venules. Furthermore, swelling of hepatocytes and capillarization of hepatic sinusoids (loss of endothelial fenestrations and collagen deposition in the space of Disse) add to the increased vascular resistance. Although architectural changes are most important, it has become clear that also a variable dynamic component significantly contributes to the increased hepatic vascular tone which can be reduced by 20 to 30% with pharmacological agents (Bhathal and Grossmann,1985; Reichen and Le,1986). The dynamic part of hepatic resistance is caused by active contraction and/or inadequate relaxation of contractile cells in liver blood vessels (Shah et al.,1998). It is assumed that an imbalance between endogenous vasoconstrictors such as endothelin-1, angiotensin II, α-adrenergic stimuli, and others on one hand and vasodilators including nitric oxide (NO) and carbon monoxide (CO) on the other hand, is responsible for the augmented intrahepatic vascular tone.

CONTRACTILE CELLS WHICH COULD BE INVOLVED IN PORTAL HYPERTENSION

  1. Top of page
  2. Abstract
  3. PORTAL HYPERTENSION
  4. CONTRACTILE CELLS WHICH COULD BE INVOLVED IN PORTAL HYPERTENSION
  5. CONTRACTILE APPARATUS OF HSC
  6. MECHANISMS OF HSC CONTRACTION AND RELAXATION
  7. WHICH SUBSTANCES INDUCE CONTRACTION/RELAXATION OF HSC?
  8. CONCLUSIONS
  9. LITERATURE CITED

There are several potential sites for sinusoidal blood flow regulation. Portal, central, and hepatic venules, and hepatic arterioles contain smooth muscle cells in their walls and they respond to contractile agents (McCuskey,2000). The major site for sinusoidal blood flow regulation however is the sinusoid itself. Sinusoids are lined by different cells: sinusoidal endothelial cells, Kupffer cells and hepatic stellate cells (HSC). Even though it has been suggested that sinusoidal endothelial cells and Kupffer cells may contract or swell thereby regulating sinusoidal blood flow, HSC are now regarded as the principle cells involved in sinusoidal blood flow regulation. Several ultrastructural and physiological features of HSC are similar to pericytes in other organs, suggesting that HSC may function as liver-specific pericytes (Pinzani et al.,1992; Pinzani,1995). Stellate cells are located in the perisinusoidal space of Disse beneath the endothelial barrier. They have long cytoplasmic processes that run parallel to the sinusoidal endothelial wall. Second order branches sprout out from the processes, embrace the sinusoid and penetrate between hepatocytes reaching neighboring sinusoids (Burt et al.,1993). Hepatic stellate cells are in close contact with nerve endings, some of which contain neuropeptides such as substance P, neuropeptide Y, somatostatin, and calcitonin gene-related peptide (Stoyanova and Gulubova,2000). The exact meaning of this remains to be elucidated, but it can be speculated that HSC could be involved in neurotransmission.

In normal liver, HSC are implicated in several important functions (Geerts,2001). Quiescent HSC play a key role in the intrahepatic uptake, storage, and release of vitamin A. Another hallmark of HSC in normal liver is the regulation of extracellular matrix turnover in the space of Disse by secreting correct amounts of a limited number of extracellular matrix molecules, and by releasing matrix metalloproteinases and their inhibitors. A third characteristic of quiescent HSC is the secretion of several growth factors including hepatocyte growth factor, vascular endothelial growth factor, endothelin-1, insulin-like growth factor II, transforming growth factor-β, nerve growth factor, neurotrophin, and so on. Finally, both the three dimensional structure and some of the ultrastructural characteristics of HSC are similar to pericytes, regulating blood flow in other organs (Pinzani et al.,1992; Pinzani,1995). Although some arguments are against, most data obtained from in vivo experiments indicate that HSC are implicated in the regulation of sinusoidal tone and may play a role in blood flow regulation in normal liver (Reynaert et al.,2002; Rockey,2001).

After acute or chronic liver injury of any etiology, HSC are activated and undergo a process of transdifferentiation leading to a myofibroblastic phenotype with proliferative, fibrogenic, and contractile properties (Friedman,2000). Morphologically, activated HSC are characterized by loss of vitamin A droplets, and a myofibroblast-like cell shape with a well developed stress fiber cytoskeleton, including de novo expression of α-smooth muscle actin. Furthermore, the expression of intermediate filaments is changed by cell activation. Functionally, activated HSC are characterized by increased proliferation and contractility, release of pro-inflammatory, pro-fibrogenic, and pro-mitogenic cytokines, migration to sites of injury, increased production of extracellular matrix components and alterations in matrix protease activity providing the fundamental needs for tissue repair. Several investigators have shown that activated HSC contract in response to various agents of which endothelin-1 is the strongest, and that some agents, e.g., NO, promote relaxation of HSC. In fact, both the anatomical location of HSC and the capacity to contract or relax in response to various vasoactive mediators suggest that these cells may play a role in modulating intrahepatic vascular resistance and blood flow at the sinusoidal level (Ramadori,1991; Pinzani et al.,1992; Pinzani,1995). Because contractility of HSC is important in sinusoidal blood flow regulation, we will focus on this phenomenon.

CONTRACTILE APPARATUS OF HSC

  1. Top of page
  2. Abstract
  3. PORTAL HYPERTENSION
  4. CONTRACTILE CELLS WHICH COULD BE INVOLVED IN PORTAL HYPERTENSION
  5. CONTRACTILE APPARATUS OF HSC
  6. MECHANISMS OF HSC CONTRACTION AND RELAXATION
  7. WHICH SUBSTANCES INDUCE CONTRACTION/RELAXATION OF HSC?
  8. CONCLUSIONS
  9. LITERATURE CITED

To be able to contract, a cell needs a contractile apparatus including functional contractile filaments. The cytoskeleton of a cell consists of three different types of cytoskeletal filaments: microfilaments or actin filaments, intermediate filaments, and microtubules. The most important functions of the cytoskeleton are structural support for the cytoplasmatic and nuclear membrane (intermediate filaments), intracellular transport (microtubules) and determination of cell shape, and cell migration and cell contraction (actin filaments). However, cytoskeletal filaments are ineffective on their own, and need accessory proteins for controlled assembly and linkage to other cell components. Motor proteins, including myosin, are the principal accessory proteins for actin-mediated cell contraction. Microtubules and intermediate filaments are not directly involved in cell contraction and will, therefore, not be discussed in this review.

As stated above, actin filaments play a major role in cell contraction. Actin monomers aggregate into oligomers of 3 to 5 monomers, which in turn elongate into long F-actin filaments (Lehman et al.,1995). The formation of long actin filaments is a dynamic process of assembly, elongation, dissociation, branching, and stabilization, which is regulated by multiple proteins, including actin related protein 2/3, profilin, cofilin, and gelsolin. By changing actin polymerization, actin generates forces on the cell membrane which results in cell shape changes and cell movement. Interaction of myosin and actin results in cell contraction. Myosins, actin-based molecular motors, are ubiquitously expressed as multiple isoforms in all eukaryotic cells. In general, myosin is composed of heavy chains and several light chain subunits. Myosin heavy chain is typically constructed of three functional subdomains: the motor domain which interacts with actin and binds ATP, the neck domain which binds myosin or calmodulin light chains, and the tail domain which serves to anchor and position the motor domain (Theriot,2002).

The human myosin family is divided into 12 classes based on the primary structure of the myosin heavy chain genes (Berg et al.,2001). To date, myosin I, II, and V have been well characterized, while the functions and biochemical properties of other myosins remain largely unknown. Myosin I, a single-headed, nonfilamentous member of the myosin family, can bind calmodulin light chain in the neck region. It is thought that myosin I is a key player for cortical membrane tension, endocytosis and endocytic trafficking, signal transduction, and membrane ruffling (Dai et al.,1999). Myosin V is a dimeric, nonfilamentous member of the myosin family, which can bind calmodulin light chain in the neck region. Myosin V is thought to play a role in transport a variety of intracellular cargo along actin (Reck-Peterson et al.,2000; Vale,2003). Myosin II is the most characterized member of the myosin family. It is two-headed and can form filaments. It is composed of two heavy chains, two nonphosphorylatable essential light chains, and two phosphorylatable regulatory light chains. Myosin II has, at least, 13 kinds of heavy chain genes including 6 skeletal, 3 cardiac, 1 smooth muscle, and 3 nonmuscle myosin heavy chain genes. Myosin II light chain also has 5 alkali light chain genes and 5 regulatory light chain genes. Myosin II can interact with actin and is in this way responsible for cell contraction. The exact mechanism by which the interaction between myosin and actin causes contraction is beyond the scope of this review. In short, the myosin head of a heavy chain binds an actin subunit and “walks” to the next actin subunit by changing its shape using the energy liberated by hydrolysis of one ATP molecule (Rayment et al.,1993).

Information on the expression and functions of myosins by HSC is scarce. HSC have been shown to express alpha smooth muscle myosin heavy chain (MYH 11), perinatal skeletal myosin heavy chain (MYH 8), adult skeletal IIa (MYH 2), and IId (MYH 1) myosin heavy chains (Ogata et al.,1993). In addition, we recently demonstrated the presence of nonmuscle myosin heavy chain IIA (MYH 9) and IIB (MYH 10) in quiescent mouse HSC. Whereas myosin heavy chain IIA remained constant during activation, myosin heavy chain IIB was up-regulated. We also established that myosin heavy chain IIA was important for cell contraction (Liu et al.,2007).

Traditionally, sarcomeric myosins have been thought to be restricted to striated muscle cells. Thus, HSC might be equipped with skeletal myosins which participate in HSC contraction. Although the mechanisms by which myosin II proteins are involved in the contraction of HSC have not been clarified, it has been assumed that, in analogy to other myofibroblast-like cells, myosin II is a key player for contraction of activated HSC.

MECHANISMS OF HSC CONTRACTION AND RELAXATION

  1. Top of page
  2. Abstract
  3. PORTAL HYPERTENSION
  4. CONTRACTILE CELLS WHICH COULD BE INVOLVED IN PORTAL HYPERTENSION
  5. CONTRACTILE APPARATUS OF HSC
  6. MECHANISMS OF HSC CONTRACTION AND RELAXATION
  7. WHICH SUBSTANCES INDUCE CONTRACTION/RELAXATION OF HSC?
  8. CONCLUSIONS
  9. LITERATURE CITED

Activation of myosin II is regulated by Ca2+-dependent and independent mechanisms (Ganitkevich et al.,2002; Pfitzer,2001). Intracellular Ca2+, whether released from endoplasmatic reticulum by inositol 1,4,5-trisphosphate (IP3) or by Ca2+ influx, binds to calmodulin. The Ca2+-calmodulin complex then binds the enzyme myosin light chain kinase, which becomes activated and phosphorylates myosin regulatory light chain. In turn, phosphorylated myosin light chain activates contraction. A second mechanism of contraction is Ca2+-independent: Rho-kinase, a small GTPase, regulates myosin light chain phosphorylation by inhibiting myosin phosphatase and also by direct phosphorylation of myosin light chain (Kureishi et al.,1997; Amano et al.,2000; Somlyo and Somlyo,2000). When myosin phosphatase is inactive, myosin light chain phosphorylation and, thus, myosin activity and contractility increases. It is clear that both Ca2+-dependent and independent mechanisms are involved in HSC contraction. It has been speculated that, as HSC are activated and exhibit “smooth muscle like features,” Ca2+ signaling could become more important (Yee,2001). However, this has been challenged recently as it was demonstrated that both pathways are necessary for maximal contraction of HSC, but that Ca2+-independent pathways predominate in activated HSC and in cirrhotic liver (Laleman et al.,2007a).

Calcium Channels

At least two different types of Ca2+ channels have been described in activated HSC: Voltage operated calcium channels and store operated channels. It has been demonstrated that the activation of HSC is associated with both an up-regulation of L-type voltage-operated Ca2+ channels that mediate Ca2+ influx and KCl-induced contraction (Bataller et al.,2001). However, as HSC have not been shown to be excitable, it will be important to establish the physiological relevance of these channels. Some of the changes in [Ca2+]i are mediated by means of store operated calcium channels (Tao et al.,1999). Depletion of Ca2+ in the [Ca2+]i stores will lead to activation of these calcium channels. Furthermore, some G-protein coupled receptors, such as endothelin can directly activate receptor gated Ca2+ channels, but this mechanism has not been proven to be present in HSC. Whatever the mechanism of increased [Ca2+]i, it will result in cell contraction. Indeed, it has been demonstrated that reductions in HSC area, a marker of contractile force generation, correlate with the height of the increased [Ca2+]i peak (Bataller et al.,1998; Pinzani et al.,1992).

Rho

Rho is a member of the Ras superfamily (Sah et al.,2000). Rho activates Rho kinase which regulates cell morphology through organizing the actin cytoskeleton and controlling the actomyosin-dependent cellular processes (Ridley and Hall,1992). Rho kinase has been shown to participate in the induction of stress fibers, focal adhesion formation and cell contraction (Uehata et al.,1997; Amano et al.,2000). In HSC, Rho and Rho kinase have been shown to enhance myosin activation, suggesting a role in the generation of contractile force (Yanase et al.,2000). This finding has been supported by the demonstration that Rho signaling pathways regulate agonist (e.g., endothelin-1) induced contraction (Yanase et al.,2000).

Protein Kinase C

Activation of protein kinase C in smooth muscle results in a slowly developing and sustained contractile response, at constant Ca2+ without any change in myosin light chain phosphorylation (Forder et al.,1985; Chatterjee and Tejada,1986). The production of a sustained response by protein kinase C appears to involve phosphorylation of intermediate filaments (e.g., desmin, synemin), caldesmon, and a small number of unidentified low molecular weight proteins (Rasmussen et al.,1987). The role of protein kinase C in HSCs contraction is supported by the demonstration that inhibition of protein kinase C prevents the response to endothelin-1 (Kawada et al.,1993). In comparison to contraction, little is known about the signaling pathways which regulate HSC relaxation.

Cyclic Adenosine Monophosphate (cAMP)

Cyclic adenosine monophosphate (cAMP) reduces HSC contraction by inactivation of myosin light chain kinase through phosphorylation of the protein (Adelstein et al.,1978). In addition, cAMP reduces Ca2+ influx, possibly by a direct effect on L-type Ca2+ channels (Rembold,1996).

Cyclic Guanosine Monophosphate (CGMP)

Cyclic guanosine monophosphate (CGMP) also promotes HSC relaxation (Kawada et al.,1993; Sakamoto et al.,1997). In smooth muscle cells, it has been shown to decrease [Ca2+]i by decreasing Ca2+ influx through inhibition of L-type Ca2+ channels, by attenuation of IP3-induced Ca2+ release from intracellular stores, and by increasing Ca2+ efflux by activation of Ca2+ ATPase (Rembold,1996).

It is clear that relaxation of HSC is also caused by inhibition of contractile mechanisms, for instance inhibition of the activation of Rho. The state of contraction/relaxation will be the result of the sum of contractile and relaxing mechanisms and their inhibition.

Although activated HSC contract in response to vasoactive substances, both in vivo and in vitro, there has been some debate whether stellate cell contraction is forceful enough to produce sinusoidal constriction. This issue was resolved in a recent study in which HSC contraction was directly quantified and was found to be greater than the sinusoidal pressure in cirrhotic rats, indicating that HSC can constrict sinusoids (Thimgan and Yee,1999).

WHICH SUBSTANCES INDUCE CONTRACTION/RELAXATION OF HSC?

  1. Top of page
  2. Abstract
  3. PORTAL HYPERTENSION
  4. CONTRACTILE CELLS WHICH COULD BE INVOLVED IN PORTAL HYPERTENSION
  5. CONTRACTILE APPARATUS OF HSC
  6. MECHANISMS OF HSC CONTRACTION AND RELAXATION
  7. WHICH SUBSTANCES INDUCE CONTRACTION/RELAXATION OF HSC?
  8. CONCLUSIONS
  9. LITERATURE CITED

Numerous substances have been investigated in vitro, but the in vivo significance on portal pressure remains unclear for many of those (Reynaert et al.,2002). A list of substances is provided in Table 1, and we will briefly discuss some of the important ones.

Table 1. Substances investigated in vitro
AgentEffectMechanism
Endothelin-1Contraction[Ca2+]i
ThrombinContraction[Ca2+]i
Angiotensin IIContraction[Ca2+]i
VasopresssinContraction[Ca2+]i
AdenosineContraction[Ca2+]i?
Substance PContraction[Ca2+]i
Leukotriene D4Contraction[Ca2+]i
PGF2 / thromboxaneContraction[Ca2+]i
Lysophosphatidic acidContractionRho-kinase
NORelaxationcGMP
CORelaxationcGMP
H2SRelaxation 
Atrial Natriuretic PeptideRelaxationcGMP/[Ca2+]i
AdrenomedullinRelaxationcAMP
SomatostatinRelaxation[Ca2+]i,/Rho kinase?
Agents increasing cAMP/cGMPRelaxationcAMP/cGMP
PGI2/ PGE2RelaxationcAMP
Y-27632 (Rho kinase inhibitor)RelaxationRho kinase

One of the most potent and certainly most studied vasoactive modulators of HSC are endothelins. Endothelins act through at least two G-protein coupled receptors, termed endothelin receptor subtype A (ETA) and B (ETB). Both receptors are expressed by HSC (Housset et al.,1993). In cultured HSC, endothelin-1 induced a dose-dependent increase in [Ca2+]i both by release of Ca2+ from intracellular stores and by stimulating Ca2+ influx coupled with contraction of the cells (Pinzani et al.,1992). In cirrhotic patients, a direct relationship between endothelin receptor mRNA abundance and the degree of portal hypertension has been documented (Leivas et al.,1998).

It is known for many years now that the renin angiotensin system is implicated in portal hypertension and its complications (Bosch et al.,1980). More recently, studies have shown the presence of AT1 receptors in activated rat and human HSC (Bataller et al.,2000; Zhang et al.,2003). Activation of AT1 receptors by angiotensin II elicited a marked contraction of activated human HSCs by an increase in intracellular [Ca2+]i (Bataller et al.,2000). The same group of investigators demonstrated that activated HSC express renin, angiotensinogen, and angiotensin converting enzyme and synthesize angiotensin II (Bataller et al.,2003). These observations suggested that the local renin angiotensin system could be implicated in portal hypertension.

Nitric oxide is an omnipresent messenger molecule involved in various cellular processes, including neurotransmission, inflammation, and regulation of vascular tone. It is a potent vasodilator, acting in a paracrine manner by directly stimulating soluble guanylate cyclase, resulting in increased levels of cGMP and consequently decreased [Ca2+]i and vasorelaxation (Wiest and Groszmann,1999). In cirrhosis, systemic and splanchnic vascular NO production is increased, but intrahepatic NO production is deficient. Nitric oxide was shown to modulate the contractile effect of endothelin-1 on cultured HSC (Kawada et al.,1993). Moreover, an intrahepatic NO-donor decreased HSC contractility in vitro and reduced portal hypertension in cirrhotic rats (Laleman et al.,2007b). These observations suggest a role of HSC in NO-induced regulation of intrahepatic vascular resistance (Rockey and Chung,1995).

Carbon monoxide is a gaseous molecule produced by degradation of heme, mediated by activity of heme oxygenase (HO). Carbon monoxide activates soluble guanylate cyclase to produce cGMP, thereby causing smooth muscle relaxation. Two isoforms (HO-1 and HO-2) are expressed in normal liver (HO-1 in Kupffer cells and HO-2 in hepatocytes), but both isoforms were undetectable in normal rat HSC (Goda et al.,1998). Heme oxygenase-1 gene expression was up-regulated in hepatocytes and Kupffer cells of rats and patients with cirrhosis and portal hypertension (Fernandez and Bonkovsky,1999; Makino et al.,2001; Matsumi et al.,2002). In rats, increased HO-1 expression resulted in increased CO production and a reduction of hepatic vascular resistance (Wakabayashi et al.,1999). In vivo microscopy demonstrated that HO-1 directly acts by means of HSC in rat livers (Rensing et al.,2002). HO-1 seems to play a role in counteracting the vasoconstrictor effect of endothelin-1 in the stressed liver. Up to now, it remains unknown whether this mediator system is relevant in patients with portal hypertension.

Somatostatin reduces portal pressure by several mechanisms (Reynaert and Geerts,2003). We have shown that, on top of the effects on portal blood flow, activation of the somatostatin receptor subtype 1 caused partial inhibition of endothelin-1–induced contraction of rat HSC (Reynaert et al.,2001). More recently, we were able to demonstrate in vivo that somatostatin, but not octreotide, caused dilatation of hepatic sinusoids at the site of HSC, thereby reducing intrahepatic vascular resistance (Van Heule et al.,2005).

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. PORTAL HYPERTENSION
  4. CONTRACTILE CELLS WHICH COULD BE INVOLVED IN PORTAL HYPERTENSION
  5. CONTRACTILE APPARATUS OF HSC
  6. MECHANISMS OF HSC CONTRACTION AND RELAXATION
  7. WHICH SUBSTANCES INDUCE CONTRACTION/RELAXATION OF HSC?
  8. CONCLUSIONS
  9. LITERATURE CITED

Portal hypertension, which is caused by both increased blood flow and increased intrahepatic vascular resistance, is one of the most feared complications of cirrhosis. Activated HSC have been implicated in the increased intrahepatic vascular tone. The cells are in an favorable anatomical location and have the necessary machinery for contraction. Activated stellate cells respond to various vasoactive substances, which play a role in the pathophysiology of portal hypertension. Therefore, HSC are now regarded as potential therapeutic targets for treating portal hypertension.

LITERATURE CITED

  1. Top of page
  2. Abstract
  3. PORTAL HYPERTENSION
  4. CONTRACTILE CELLS WHICH COULD BE INVOLVED IN PORTAL HYPERTENSION
  5. CONTRACTILE APPARATUS OF HSC
  6. MECHANISMS OF HSC CONTRACTION AND RELAXATION
  7. WHICH SUBSTANCES INDUCE CONTRACTION/RELAXATION OF HSC?
  8. CONCLUSIONS
  9. LITERATURE CITED