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Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature

Departments of ¹Cell and Developmental Biology, ²Medicine, and ³Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee

Submitted 22 January 2007 ; accepted in final form 12 November 2007

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^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^Ex2/+ mutant mice. These findings indicate that the pulmonary endothelium is a target of abnormal BMP signaling in Bmpr2^Ex2/+ mutant mice and suggest that endothelial dysfunction contributes to their increased susceptibility to hypoxic pulmonary hypertension.

bone morphogenetic protein receptors; endothelial dysfunction; pulmonary hypertension; endothelial nitric oxide synthase

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