Autocrine angiotensin system regulation of bovine aortic endothelial cell migration and plasminogen activator involves modulation of proto-oncogene pp60c-src expression

Abstract

Rapid endothelial cell migration and inhibition of thrombosis are critical for the resolution of denudation injuries to the vessel wall. Inhibition of the endothelial cell autocrine angiotensin system, with either the angiotensin-converting enzyme inhibitor lisinopril or the angiotensin II receptor antagonist sar1, ile8-angiotensin II, leads to increased endothelial cell migration and urokinase-like plasminogen activator (u-PA) activity (Bell, L., and J.A. Madri. 1990. Am. J. Pathol. 137:7-12). Inhibition ut the autocrine angiotensin system with the converting-enzyme inhibitor or the receptor antagonist also leads to increased expression of the proto-oncogene c-src: pp60c-src mRN A increased 1 1-fold, c-src protein 3-fold, and c-src kinase activity 2-3-fold. Endothelial cell expression of c-src was constitutively elecated after stable infection with a retroviral vector containing the c-src coding sequence. Constitutively increased c-src kinase activity reconstituted the increases in migration and u-PA observed with angiotensin system interruption. Antisera to bovine u-PA blocked the increase in migration associated with increased c-src expression. These data suggest that increases in endothelial cell migration and plasminogen activator after anuiotensin system inhibition are at least partially pp60c-src mediated. Elevated c-src expression with angiotensin system inhibition may act to enhance intimai wound closure and to reduce luminal thrombogenicity in vivo.