Title

Increased Susceptibility to Hypoxic Pulmonary Hypertension in Bmpr2 Mutant Mice is Associated with Endothelial Dysfunction in the Pulmonary Vasculature

Document Type

Article

Publication Date

1-1-2008

Published In / Presented At

American Journal of Physiology. Lung, Cellular and Molecular Physiology

Disciplines

Animal Sciences | Cell Anatomy | Genetics | Medicine and Health Sciences

Abstract

Patients with familial pulmonary arterial hypertension inherit heterozygous mutations of the type 2 bone morphogenetic protein (BMP) receptor BMPR2. To explore the cellular mechanisms of this disease, we evaluated the pulmonary vascular responses to chronic hypoxia in mice carrying heterozygous hypomorphic Bmpr2 mutations (Bmpr2 delta Ex2/+). These mice develop more severe pulmonary hypertension after prolonged exposure to hypoxia without an associated increase in pulmonary vascular remodeling or proliferation compared with wild-type mice. This is associated with defective endothelial-dependent vasodilatation and enhanced vasoconstriction in isolated intrapulmonary artery preparations. In addition, there is a selective decrease in hypoxia-induced, BMP-dependent, endothelial nitric oxide synthase expression and Smad signaling in the intact lungs and in cultured pulmonary microvascular endothelial cells from Bmpr2 delta Ex2/+ mutant mice. These findings indicate that the pulmonary endothelium is a target of abnormal BMP signaling in Bmpr2 delta Ex2/+ mutant mice and suggest that endothelial dysfunction contributes to their increased susceptibility to hypoxic pulmonary hypertension.

Rights

Copyright held by American Physiological Society

DOI

10.1152/ajplung.00034.2007

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