Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension

Anderson, Lynda; Lowery, Jonathan W.; Frank, David B.; Novitskaya, Tatiana; Jones, Mark T.; Mortlock, Douglas P.; Chandler, Ronald L.; Caestecker, Mark P. de

doi:10.1152/ajpregu.00534.2009

Cited by 63 publications

(74 citation statements)

References 32 publications

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“…This is consistent with published data indicating that both Id1 and Id3 are transcriptional targets of BMP-activated SMADs in a variety of cells types (27). Furthermore, since our laboratory has previously shown that hypoxia-induced PH is dependent on intact BMP signaling (2,8,9), and since ID1-and ID3-positive VSMCs are also closely associated with BMP-2-and BMP-4-expressing cells in small peripheral vessels and alveoli of the hypoxic lung (2,8), these findings are consistent with the hypothesis that hypoxia induces VSMC expression of ID1 and ID3 in the intact pulmonary vasculature in a BMP-dependent fashion. However, while Id2 is also a bona fide BMP target gene in a variety of different cell types (15,20,37), its expression is unaffected by hypoxia or BMP treatment in these cultured mouse PASMCs.…”

Section: Discussionsupporting

confidence: 93%

“…As reported previously (2,8,9,22), this revealed activation of the BMP pathway by hypoxia, as indicated by increased COOHterminal phosphorylation of the receptor-activated SMADs 1, 5, and 8 (pS1/5/8) (Supplemental Fig. S8, A and B).…”

Section: Regulation Of Pulmonary Id1-3 Expression Levels By Hypoxiasupporting

confidence: 84%

“…For example, the alkaloid toxin monocrotaline transiently increases phosphorylation of SMAD1/5/8 in cultured human ECs (32), but can lead to both increased (33) and decreased (21,28,50) pulmonary SMAD1/ 5/8 phosphorylation in rats in vivo. In response to chronic hypoxia, pulmonary SMAD1/5/8 phosphorylation is unchanged in rats (21), while it is increased in mice (2,8,9,22). Our laboratory has previously shown, using a genetics-based approach, that hypoxia-induced PH, VSMC proliferation, and pulmonary vascular remodeling are dependent on an intact BMP signaling pathway in mice (2,8,9).…”

Section: Discussionmentioning

confidence: 96%

“…Vascular cell proliferation was assessed after 1 wk of hypoxia, because significant hypoxia-induced proliferation is not observed at the 3-wk time point. Alveolar density (number of alveoli/mm 2 ) and peripheral vessel density (number of peripheral vessels/100 alveoli) were scored from 10 ϫ200 fields while blinded to genotype, as described (2).…”

Section: Methodsmentioning

confidence: 99%

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ID family protein expression and regulation in hypoxic pulmonary hypertension

Lowery¹,

Frump²,

Anderson

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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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...

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Section: Discussionsupporting

confidence: 93%

Section: Regulation Of Pulmonary Id1-3 Expression Levels By Hypoxiasupporting

confidence: 84%

Section: Discussionmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

ID family protein expression and regulation in hypoxic pulmonary hypertension

Lowery¹,

Frump²,

Anderson

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

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show abstract

“…Several studies revealed that there was interaction between BMP2 and BMP4. 16,17 We found that BMP4 treatment did not affect BMP2 protein expression in cardiomyocytes ( Figure S11C). …”

Section: Bmp4 Induces Cardiomyocyte Hypertrophy and Apoptosis Throughmentioning

confidence: 93%

Bone Morphogenetic Protein-4 Mediates Cardiac Hypertrophy, Apoptosis, and Fibrosis in Experimentally Pathological Cardiac Hypertrophy

et al. 2013

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Identifying the key factor mediating pathological cardiac hypertrophy is critically important for developing the strategy to protect against heart failure. Bone morphogenetic protein-4 (BMP4) is a mechanosensitive and proinflammatory gene. In this study, we investigated the role of BMP4 in cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy. The in vivo pathological cardiac hypertrophy models were induced by pressure-overload and angiotensin (Ang) II constant infusion in mice, and the in vitro model was induced by Ang II exposure to cultured cardiomyocytes. The expression of BMP4 increased in pressure overload, Ang II constant infusion-induced pathological cardiac hypertrophy, but not in swimming exercise-induced physiological cardiac hypertrophy in mice. BMP4 expression also increased in Ang II–induced cardiomyocyte hypertrophy in vitro. In turn, BMP4 induced cardiomyocyte hypertrophy, apoptosis, and cardiac fibrosis, and these pathological consequences were inhibited by the treatment with BMP4 inhibitors noggin and DMH1. Moreover, Ang II–induced cardiomyocyte hypertrophy was inhibited by BMP4 inhibitors. The underlying mechanism that BMP4-induced cardiomyocyte hypertrophy and apoptosis was through increasing NADPH oxidase 4 expression and reactive oxygen species-dependent pathways. Lentivirus-mediated overexpression of BMP4 recapitulated hypertrophy and apoptosis in cultured cardiomyocytes. BMP4 inhibitor DMH1 inhibited pressure overload–induced cardiac hypertrophy in mice in vivo. The plasma BMP4 level of heart failure patients was increased compared with that of subjects without heart failure. In summary, we conclude that BMP4 is a mediator and novel therapeutic target for pathological cardiac hypertrophy.

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Experimental and Transgenic Models of Pulmonary Hypertension

West

Hemnes

2011

Comprehensive Physiology

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Pulmonary hypertension in human patients can result from increased pulmonary vascular tone, pressure transferred from the systemic circulation, dropout of small pulmonary vessels, occlusion of vessels with thrombi or intimal lesions, or some combination of all of these. Different animal models have been designed to reflect these different mechanistic origins of disease. Pulmonary hypertension models may be roughly grouped into tone-related models, inflammation-related models, and genetic models with unusual or mixed mechanism. Models of tone generally use hypoxia as a base, and then modify this with either genetic modifications (SOD, NOS, and caveolin) or with drugs (Sugen), although some genetic modifications of tone-related pathways can result in spontaneous pulmonary hypertension (Hph-1). Inflammation-related models can use either toxic chemicals (monocrotaline, bleomycin), live pathogens (stachybotrys, schistosomiasis), or genetic modifications (IL-6, VIP). Additional genetic models rely on alterations in metabolism (adiponectin), cell migration (S100A4), the serotonin pathway, or the BMP pathway. While each of these shares molecular and pathologic symptoms with different classes of human pulmonary hypertension, in most cases the molecular etiology of human pulmonary hypertension is unknown, and so the relationship between any model and human disease is unclear. There is thus no best animal model of pulmonary hypertension; instead, investigators must select the model most related to the specific pathology they are studying.

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Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension

Cited by 63 publications

References 32 publications

ID family protein expression and regulation in hypoxic pulmonary hypertension

ID family protein expression and regulation in hypoxic pulmonary hypertension

Bone Morphogenetic Protein-4 Mediates Cardiac Hypertrophy, Apoptosis, and Fibrosis in Experimentally Pathological Cardiac Hypertrophy

Experimental and Transgenic Models of Pulmonary Hypertension

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