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...
The bone morphogenetic protein (BMP) type 2 receptor ligand, Bmp2, is upregulated in the peripheral pulmonary vasculature during hypoxia-induced pulmonary hypertension (PH). This contrasts with the expression of Bmp4, which is expressed in respiratory epithelia throughout the lung. Unlike heterozygous null Bmp4 mice (Bmp4(LacZ/+)), which are protected from the development of hypoxic PH, mice that are heterozygous null for Bmp2 (Bmp2(+/-)) develop more severe hypoxic PH than their wild-type littermates. This is associated with reduced endothelial nitric oxide synthase (eNOS) expression and activity in the pulmonary vasculature of hypoxic Bmp2(+/-) but not Bmp4(LacZ/+) mutant mice. Furthermore, exogenous BMP2 upregulates eNOS expression and activity in intrapulmonary artery and pulmonary endothelial cell preparations, indicating that eNOS is a target of Bmp2 signaling in the pulmonary vasculature. Together, these data demonstrate that Bmp2 and Bmp4 exert opposing roles in hypoxic PH and suggest that the protective effects of Bmp2 are mediated by increasing eNOS expression and activity in the hypoxic pulmonary vasculature.
To address this, we evaluated pulmonary expression of ID proteins in a mouse model of hypoxia-induced PH. There is selective induction of ID1 and ID3 expression in hypoxic pulmonary vascular smooth muscle cells (VSMCs) in vivo, and ID1 and ID3 expression are increased by hypoxia in cultured pulmonary VSMCs in a BMPdependent fashion. ID4 protein is barely detectable in the mouse lung, and while ID2 is induced in hypoxic peripheral VSMCs in vivo, it is not increased by hypoxia or BMP signaling in cultured pulmonary VSMCs. In addition, the PH response to chronic hypoxia is indistinguishable between wild type and Id1 null mice. This is associated with a compensatory increase in ID3 but not ID2 expression in pulmonary VSMCs of Id1 null mice. These findings indicate that ID1 is dispensable for mounting a normal pulmonary vascular response to hypoxia, but suggest that ID3 may compensate for loss of ID1 expression in pulmonary VSMCs. Taken together, these findings indicate that ID1 and ID3 expression are regulated in a BMP-dependent fashion in hypoxic pulmonary VSMCs, and that ID1 and ID3 may play a cooperative role in regulating BMP-dependent VSMC responses to chronic hypoxia. 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. However, interference with BMPR2 signaling in vascular smooth muscle cells (VSMCs) by overexpression of a dominant negative BMPR2 mutation also promotes spontaneous PH in mice (45). Furthermore, conditional deletion of the BMP type 1 receptor ALK3 in VSMCs reduces hypoxic pulmonary vascular remodeling and VSMC proliferation (7). These findings indicate that defective BMPR2 signaling influences both the EC and VSMC compartments in the pulmonary vasculature. However, the relationship between defective BMP signaling and vascular cell phenotypes in HPAH is complex and poorly understood (23).One approach to explore this has been to investigate the downstream signaling pathways that mediate the effects of BMP receptor mutations in different pulmonary vascular cell types. These studies also enable us to interrogate PH-associated alterations in BMP signaling that occur in the pulmonary vasculature in the absence of BMPR2 mutations. Activation of the BMP receptors leads to COOH-termi...
Patients with Familial Pulmonary Hypertension have mutations in the BMP receptor, BMPR2, but it is unknown how these mutations cause disease. These observations also raise questions as to the role of BMPR2 signaling in other forms of pulmonary hypertension (PH). To address this, we evaluated the regulation and function of Bmpr2 ligands in a mouse model of hypoxic PH. Pulmonary Bmp2 and Bmp4 are up‐regulated by hypoxia: Bmp2 is up‐regulated in the peripheral pulmonary vasculature, while Bmp4 is widely expressed in respiratory epithelia. Loss of hypoxia‐induced Bmp4 in Bmp4+/− mice is associated with reduced PH and decreased pulmonary vascular remodeling. This contrasts with Bmpr2ΔEx2/+ mice which show greater susceptibility to hypoxic PH, and suggests that an alternative ligand regulates Bmpr2‐dependent effects in the vasculature. Unlike Bmp4+/− mice, Bmp2+/− mice develop more severe hypoxic PH than wild type littermates. There is also reduced eNOS expression and activity in the pulmonary vasculature of hypoxic Bmp2+/−, but not Bmp4+/− mice. Bmp2 also up‐regulates eNOS expression and activity in intrapulmonary artery and endothelial cell preparations, indicating that eNOS is a target of Bmp2 in the pulmonary vasculature. These data indicate that Bmp2 and Bmp4 exert opposing roles in hypoxic PH, and suggest that protective effects of Bmp2 are mediated by increasing eNOS activity in the pulmonary vasculature.
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