Abstract
The molecular basis of the vascular wall abnormalities that contribute to development of portal hypertension are an area of active investigation. Studies to date suggest that diminution in eNOS-derived NO production in liver contributes to this process by causing increased intrahepatic resistance. This process seems to be mediated through inhibitory posttranslational regulatory mechanisms of eNOS. Endothelin-1 signaling is also increased in the intrahepatic vasculature. The mechanisms responsible for increased ET-1 signaling include increased ET-1 production and increased ET-A receptor expression, particularly within hepatic stellate cells, although the stimulus responsible for activation of the ET-1 system remains uncertain. In the splanchnic circulation, increases in eNOS-derived NO contribute to increased portal venous inflow through transcriptional and posttranslational regulation of eNOS. Development of the porto-systemic collateral circulation characteristic of portal hypertension occurs through a combination of NO-dependent dilation of preexisting vessels and through growth factor-mediated angiogenesis and neovascularization (Fig. 3). Further studies in vascular wall biology are continuing to elucidate more clearly the molecular mechanisms of portal hypertension. The mechanism by which eNOS-derived NO production is increased in the splanchnic arteriolar endothelial cell but decreased in the liver endothelial cell and the role of specific ET receptor subtypes in the mechanism of activation of the ET-1 system and its effect on contractile cells in liver cirrhosis are areas that require further investigation. Further studies are needed to determine the intrahepatic site of pressure and perfusion regulation, be it the hepatic sinusoid and its unique, specialized cell types or the endothelial and smooth muscle cells in the hepatic and portal venules. The role of more recently delineated vasoactive pathways such as urotensin-II/GPR 142 and anandamide/CB1 receptor90 in portal hypertension must be examined. Most importantly, future studies must focus on novel experimental therapies, using pharmacologic and genetic approaches to modulate these vascular biologic systems and thereby to ameliorate complications and symptoms relating to portal hypertension in patients with cirrhosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 629-644 |
| Number of pages | 16 |
| Journal | Clinics in Liver Disease |
| Volume | 5 |
| Issue number | 3 |
| State | Published - 2001 |
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ASJC Scopus subject areas
- Hepatology
Cite this
Cellular and molecular basis of portal hypertension. / Shah, Vijay.
In: Clinics in Liver Disease, Vol. 5, No. 3, 2001, p. 629-644.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cellular and molecular basis of portal hypertension
AU - Shah, Vijay
PY - 2001
Y1 - 2001
N2 - The molecular basis of the vascular wall abnormalities that contribute to development of portal hypertension are an area of active investigation. Studies to date suggest that diminution in eNOS-derived NO production in liver contributes to this process by causing increased intrahepatic resistance. This process seems to be mediated through inhibitory posttranslational regulatory mechanisms of eNOS. Endothelin-1 signaling is also increased in the intrahepatic vasculature. The mechanisms responsible for increased ET-1 signaling include increased ET-1 production and increased ET-A receptor expression, particularly within hepatic stellate cells, although the stimulus responsible for activation of the ET-1 system remains uncertain. In the splanchnic circulation, increases in eNOS-derived NO contribute to increased portal venous inflow through transcriptional and posttranslational regulation of eNOS. Development of the porto-systemic collateral circulation characteristic of portal hypertension occurs through a combination of NO-dependent dilation of preexisting vessels and through growth factor-mediated angiogenesis and neovascularization (Fig. 3). Further studies in vascular wall biology are continuing to elucidate more clearly the molecular mechanisms of portal hypertension. The mechanism by which eNOS-derived NO production is increased in the splanchnic arteriolar endothelial cell but decreased in the liver endothelial cell and the role of specific ET receptor subtypes in the mechanism of activation of the ET-1 system and its effect on contractile cells in liver cirrhosis are areas that require further investigation. Further studies are needed to determine the intrahepatic site of pressure and perfusion regulation, be it the hepatic sinusoid and its unique, specialized cell types or the endothelial and smooth muscle cells in the hepatic and portal venules. The role of more recently delineated vasoactive pathways such as urotensin-II/GPR 142 and anandamide/CB1 receptor90 in portal hypertension must be examined. Most importantly, future studies must focus on novel experimental therapies, using pharmacologic and genetic approaches to modulate these vascular biologic systems and thereby to ameliorate complications and symptoms relating to portal hypertension in patients with cirrhosis.
AB - The molecular basis of the vascular wall abnormalities that contribute to development of portal hypertension are an area of active investigation. Studies to date suggest that diminution in eNOS-derived NO production in liver contributes to this process by causing increased intrahepatic resistance. This process seems to be mediated through inhibitory posttranslational regulatory mechanisms of eNOS. Endothelin-1 signaling is also increased in the intrahepatic vasculature. The mechanisms responsible for increased ET-1 signaling include increased ET-1 production and increased ET-A receptor expression, particularly within hepatic stellate cells, although the stimulus responsible for activation of the ET-1 system remains uncertain. In the splanchnic circulation, increases in eNOS-derived NO contribute to increased portal venous inflow through transcriptional and posttranslational regulation of eNOS. Development of the porto-systemic collateral circulation characteristic of portal hypertension occurs through a combination of NO-dependent dilation of preexisting vessels and through growth factor-mediated angiogenesis and neovascularization (Fig. 3). Further studies in vascular wall biology are continuing to elucidate more clearly the molecular mechanisms of portal hypertension. The mechanism by which eNOS-derived NO production is increased in the splanchnic arteriolar endothelial cell but decreased in the liver endothelial cell and the role of specific ET receptor subtypes in the mechanism of activation of the ET-1 system and its effect on contractile cells in liver cirrhosis are areas that require further investigation. Further studies are needed to determine the intrahepatic site of pressure and perfusion regulation, be it the hepatic sinusoid and its unique, specialized cell types or the endothelial and smooth muscle cells in the hepatic and portal venules. The role of more recently delineated vasoactive pathways such as urotensin-II/GPR 142 and anandamide/CB1 receptor90 in portal hypertension must be examined. Most importantly, future studies must focus on novel experimental therapies, using pharmacologic and genetic approaches to modulate these vascular biologic systems and thereby to ameliorate complications and symptoms relating to portal hypertension in patients with cirrhosis.
UR - http://www.scopus.com/inward/record.url?scp=0034849461&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034849461&partnerID=8YFLogxK
M3 - Article
C2 - 11565134
AN - SCOPUS:0034849461
VL - 5
SP - 629
EP - 644
JO - Clinics in Liver Disease
JF - Clinics in Liver Disease
SN - 1089-3261
IS - 3
ER -