semaxinib and Hypertension--Portal

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.

Topics: Angiogenesis Inhibitors; Animals; Endothelium, Vascular; Hypertension, Portal; Indoles; Intestinal Mucosa; Intestines; Jejunum; Male; Microcirculation; Neovascularization, Pathologic; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Portal Pressure; Pyrroles; Rats; Up-Regulation; Vascular Endothelial Growth Factor A; Vasodilation

Portal hypertension is characterized by the development of a hyperdynamic splanchnic circulation. To determine whether this process is angiogenesis-dependent, we assessed the effects of SU5416, a specific inhibitor of VEGF receptor-2, in portal hypertensive rats.. Rats with portal hypertension induced by partial portal vein ligation were treated with SU5416 or vehicle during 5 days. Then, hemodynamic studies were performed using radioactive microspheres. Protein expressions of CD31, VEGF receptor-2 and VEGF were also determined by Western blotting.. Treatment of portal hypertensive rats with SU5416 resulted in a significant and marked decrease (by 44%) in portal venous inflow, and increases in splanchnic arteriolar resistance (by 68%) and portal venous resistance (by 93%). In addition, SU5416 administration significantly inhibited the formation of portal-systemic collateral vessels (52% inhibition), as well as the splanchnic CD31 and VEGF receptor-2 protein expressions in portal hypertensive rats, compared with those receiving vehicle.. This study demonstrates that the development of hyperdynamic splanchnic circulation and the formation of portal-systemic collateral vessels in portal hypertensive rats are angiogenesis-dependent processes that can be markedly inhibited by blockade of the VEGF signaling pathway. Therefore, modulation of angiogenesis may represent a potential target in the treatment of portal hypertension.

Topics: Angiogenesis Inhibitors; Animals; Arterioles; Collateral Circulation; Hemodynamics; Hypertension, Portal; Indoles; Male; Neovascularization, Pathologic; Platelet Endothelial Cell Adhesion Molecule-1; Portal System; Portal Vein; Protein Kinase Inhibitors; Pyrroles; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Splanchnic Circulation; Vascular Endothelial Growth Factor Receptor-2; Vascular Resistance