Hypoxia Induces Alteration of Bone Morphogenetic Protein Receptor Signaling in Pulmonary Artery Endothelial Cell

Abstract

Reduced expression of bone morphogenetic protein receptors (BMPR) has been implicated in the pathogenesis of pulmonary hypertension (PH), but changes in the intracellular signaling pathway of BMPR have not been fully understood. We hypothesized that BMPR signaling in pulmonary endothelial cells is altered during the development of PH, such as hypoxia-induced PH. We examined the expression of BMPR, BMP-regulated Smads and Id-1 in lung tissues of Sprague-Dawley rats exposed to 2 wk of hypoxia and in isolated lung vascular endothelial cells exposed to hypoxia. BMPRII was predominantly expressed in the endothelial cells (EC) of pulmonary vasculature. In hypoxic rats, reduced expression of BMPRII was observed in the EC of resistance pulmonary arteries. The expression of phosphorylated-Smad1/5/8 and Id-1 in EC was also reduced, whereas the expression of Smad1 as well as activin receptor-like kinase 1 (ALK1) was up-regulated during the development of PH. In in vitro exposure to hypoxia, the expression of mRNA transcripts for BMPRII, Smad8, and Id-1 in EC was reduced, whereas mRNA of Smad1 was not diminished. Our results suggest that hypoxia induces alteration of intracellular BMPR signaling in the EC of resistance pulmonary artery, which is involved in the pathogenesis of PH.