Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state

Abstract

increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Am J Physiol Gastrointest Liver Physiol 290: G980 -G987, 2006; doi:10.1152/ajpgi.00336.2005.-Increased nitric oxide (NO) is the main factor leading to the hyperdynamic circulation associated with advanced portal hypertension (PHT), but the initial mechanisms and the magnitude of increase in portal pressure required to trigger NO production are not known. We addressed these issues by studying systemic and splanchnic hemodynamics and endothelial NO synthase (eNOS) and VEGF expression in rats with different degrees of portal hypertension. Portal vein ligation (PVL) performed over needles of three different calibers (16-, 18-, and 20-gauge) yielded different degrees of PHT and portosystemic shunting. Compared with sham rats, all three groups of PVL rats exhibited features of hyperdynamic circulation. Rats with minimal portal hypertension (PVL with a 16-gauge needle) showed an early increase in VEGF and eNOS expression selectively at the jejunum. Immunofluorescence showed that VEGF expression was located in highly vascularized areas of the mucosa. Inhibition of VEGF signaling markedly attenuated the increase in eNOS expression. In conclusion, mild increases in portal pressure are enough to upregulate eNOS at the intestinal microcirculation, and this occurs, at least in part, through VEGF upregulation. cirrhosis; vasodilation A HALLMARK of portal hypertension (PHT) syndrome is a hyperdynamic circulatory state, characterized by splanchnic and peripheral vasodilation, increased plasma volume, and increased cardiac output (CO) (18). This hyperkinetic syndrome is the result of an increased production of vasodilators, mainly nitric oxide (NO), in the peripheral and splanchnic circulation (for a review, see Ref. 42). A number of mechanisms, including shear stress (20), bacterial translocation (39, 40), or portosystemic shunting (PSS) (1, 2), have been proposed to explain the upregulation of endothelial NO synthase (eNOS), the isoform that accounts for the increased NO production in PHT. However, it has been demonstrated that eNOS activation occurs before any of these mechanisms is present (22,43), and the signals that initially trigger NO hyperproduction in PHT are still poorly understood.The partial portal vein ligation (PVL) model has been shown to reproduce the systemic and hemodynamic abnormalities in PHT (37). Furthermore, its highly predictable chronobiology has allowed the elucidation of the sequences of events leading to hyperdynamic circulation (8,33). Thus this model also offers the opportunity to sequentially evaluate the molecular mechanisms leading to the hemodynamic abnormalities observed in hyperdynamic circulation. In that regard, a recent study from our laboratory suggested that, in the commonly used PVL model, in which portal vein stenosis is calibrated over a 20-gauge needle (37), the myogenic response that occurs in the s...

Clinical implications of the hyperdynamic syndrome in cirrhosis

“…Though the reduction in peripheral resistance is slow, compensatory mechanisms play a pivotal role in maintaining and further worsening the hyperdynamic circulation ( Fig. 1) [12][13][14][15][16]. Plasma volume expansion is relevant in these cirrhotic patients, even if distribution between the central and peripheral vascular areas is often not balanced [6,17].…”

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

“…26 NO appears to be the primary vasodilator in the arterial vasodilatation and the hyperdynamic circulatory state of liver cirrhosis. Degree of portal hypertension correlates with eNOS activation in the splanchnic circulation, in an animal model of portal hypertension 27 and is initiated by physical stimuli that induce Akt-dependent eNOS activation as well as through increased production of VEGF. [27][28][29] Thus, portal pressure itself, may be an important factor that regulates vasodilatation in the splanchnic arterial circulation by means of eNOS activation in the splanchnic circulation.…”

“…Degree of portal hypertension correlates with eNOS activation in the splanchnic circulation, in an animal model of portal hypertension 27 and is initiated by physical stimuli that induce Akt-dependent eNOS activation as well as through increased production of VEGF. [27][28][29] Thus, portal pressure itself, may be an important factor that regulates vasodilatation in the splanchnic arterial circulation by means of eNOS activation in the splanchnic circulation. 27 The formation of portosystemic collateral vessels and gastroesophageal varices are another important feature of portal hypertension that result in esophageal variceal hemorrhage.…”

“…[27][28][29] Thus, portal pressure itself, may be an important factor that regulates vasodilatation in the splanchnic arterial circulation by means of eNOS activation in the splanchnic circulation. 27 The formation of portosystemic collateral vessels and gastroesophageal varices are another important feature of portal hypertension that result in esophageal variceal hemorrhage. Recent studies have focused on the potential role of angiogenic factors in the formation of portosystemic collateral vessels in portal hypertension as well as therapeutic implications of antiangiogenic therapies.…”

Profilaxis preprimaria de la hemorragia por varices

“…El ON media los efectos endoteliales del VEGF, facilitando la proliferación de cé-lulas endoteliales y la migración, y también estimula la liberación de progenitores de células endoteliales de la mé-dula ósea, contribuyendo a la vasculogénesis (46). Por su parte, el VEGF promueve la producción de ON e induce la expresión de la eONS (47); experimentalmente se ha demostrado que un aumento leve de la presión portal estimula la producción de VEGF en la microcirculación yeyunal, y esta señal es suficiente para inducir la actividad de la eONS (48). Este conjunto de datos indica que tanto la eONS como el VEGF son dianas potenciales para modular la formación de colaterales portosistémicas (varices) en la hipertensión portal.…”