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

TLDR

Increased nitric oxide is the main driver of hyperdynamic circulation in advanced portal hypertension, yet the initial mechanisms and portal pressure threshold for NO production remain unclear. The study aimed to determine how varying degrees of portal hypertension affect systemic and splanchnic hemodynamics and the expression of endothelial NO synthase and VEGF in rats. Portal vein ligation using 16-, 18-, and 20‑gauge needles produced graded portal hypertension and portosystemic shunting, allowing assessment of hemodynamic and molecular responses. Mild portal hypertension induced hyperdynamic circulation and early upregulation of VEGF and eNOS in the jejunal microcirculation, with VEGF localized to highly vascularized mucosal areas and its inhibition blunting eNOS expression, showing that modest portal pressure elevations trigger intestinal eNOS via VEGF.

Abstract

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.