Src Kinase Activation in Pulmonary Arterial Hypertension

Abstract

Heritable Pulmonary Arterial Hypertension (HPAH) is a rare, fatal disease of the pulmonary vasculature for which there is no cure. The majority of HPAH patients inherit mutations in the BMP type 2-receptor gene, BMPR2, but how these promote pulmonary vascular disease is unclear. In this work, we show BMPR2 mutations promote Src-kinase activation pulmonary endothelial cells (PECs) isolated from Bmpr2 mutant mice. We show increased Src activation leads to endothelial barrier defects due in part to enhanced Src-mediated caveolar endocytosis and that these defects can be rescued using Src kinase inhibitors. We go on to show that pulmonary endothelial cells and late outgrowth endothelial progenitor cells isolated from idiopathic PAH patients show similar increases in Src kinase activation suggesting that Src kinase activation may be a common disease mechanism in PAH. Therefor, these studies provide evidence for the use of Src kinase inhibitors in the treatment of pulmonary arterial hypertension.