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Am J Physiol Lung Cell Mol Physiol (November 16, 2007). doi:10.1152/ajplung.00034.2007
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Submitted on January 22, 2007
Accepted on November 12, 2007

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

David B. Frank1, Jonathan W. Lowery1, Lynda Anderson2, Monique Brink2, Jeff Reese3, and Mark Peter de Caestecker4*

1 Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, United States
2 Nephrology, Vanderbilt University, Nashville, Tennessee, United States
3 Pediatrics, Vanderbilt University, Nashville, Tennessee, United States
4 Nephrology, Vanderbilt University, Nashville, Tennessee, United States; Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, United States

* To whom correspondence should be addressed. E-mail: mark.de.caestecker{at}vanderbilt.edu.

Patients with Familial Pulmonary Arterial Hypertension (FPAH) inherit heterozygous mutations of the type 2 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 following prolonged exposure to hypoxia without an associated increase in pulmonary vascular remodeling or proliferation compared to 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 eNOS 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 pulmonary endothelium is a target of abnormal BMP signaling in of Bmpr2{Delta}Ex2/+ mutant mice, and suggest that endothelial dysfunction contributes to their increased susceptibility to hypoxic pulmonary hypertension.




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