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

Abstract

de Caestecker M. Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature. Am J Physiol Lung Cell Mol Physiol 294: L98-L109, 2008. First published November 16, 2007 doi:10.1152/ajplung.00034.2007.-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/ϩ ). 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/ϩ mutant mice. These findings indicate that the pulmonary endothelium is a target of abnormal BMP signaling in Bmpr2 ⌬Ex2/ϩ 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 GENETIC STUDIES HAVE SHOWN that patients with familial pulmonary arterial hypertension (FPAH) inherit heterozygous mutations in the type 2 bone morphogenetic protein (BMP) receptor gene BMPR2 (8,17). The majority of BMPR2 mutations encode premature termination codons or amino acid substitutions in critical functional domains of the mature protein, suggesting that these give rise to receptors with complete or partial loss of function (20). Although this implies that decreased function of a single BMPR2 allele predisposes these individuals to clinical disease, the underlying mechanisms and cellular effectors of this abnormal response remain to be established.BMPR2 is a member of the transforming growth factor-␤ (TGF-␤) family of receptors (6), which act downstream of a large family of ligands, which includes BMP2, BMP4, and BMP7 (all of which are expressed in the lung; Refs. 13, 24). These ligands interact with two classes of transmembrane receptors, termed type 1 receptors, which include ALK2, 3, and 6, and type 2 receptors, which include BMPR2, ActR2A, and ActR2B. Activation of these receptors leads to phosphorylation of a subset of intracellular signaling proteins known as the receptor-activated Smads, resulting in their nuclear translocation and transactivation of target genes. Of the receptoractivated Smad proteins, Smad1, Smad5, and Smad8 are preferentially phosphorylated by BMP receptor complexes. In addition, there is evidence that these...

Echocardiography of pulmonary vascular function in asymptomatic carriers ofBMPR2mutations

“…This result agrees with recent report that BMPR2 mutant mice are more susceptible to hypoxic pulmonary hypertension [11]. Hypoxic breathing was associated with the expected decrease in a in the three study groups [10], suggesting that any intrinsic difference in pulmonary vascular compliance is overwhelmed by hypoxic pulmonary vasoconstriction.…”

Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

“…11 Some models are notable for a modest rise in baseline right ventricular (RV) pressure, 8,12 while others are not. [13][14][15] Typically, a proportional RV hypertrophic response is observed. However, there is a precedent for uncoupling of the pulmonary vascular and cardiac responses suggesting independent or tissue-specific regulatory mechanisms may be operative.…”

ID family protein expression and regulation in hypoxic pulmonary hypertension

“…hypoxia; bone morphogenetic protein signaling; ID1; ID2; ID3; vascular smooth muscle cells; endothelial cells GENETIC STUDIES IN PATIENTS with hereditary pulmonary arterial hypertension (HPAH) indicate that defective bone morphogenetic protein (BMP) type 2 receptor (BMPR2) signaling plays a critical role in promoting pulmonary hypertension (PH) and obliterative pulmonary vascular remodeling in this disease (16,25). Studies in mice carrying heterozygous null and hypomorphic germ line Bmpr2 mutations show that these mice do not develop spontaneous PH, but they have increased susceptibility to PH in response to inflammatory mediators and serotonin (22,38,39) or to chronic hypoxia (9). Conditional deletion of Bmpr2 in endothelial cells (ECs) promotes spontaneous PH in a subset of affected mice (11), indicating that defective BMPR2 signaling plays a role in regulating EC function.…”