An antiproliferative BMP-2/PPARγ/apoE axis in human and murine SMCs and its role in pulmonary hypertension

Hansmann, Georg; Perez, Vinicio A. de Jesus; Alastalo, Tero-Pekka; Alvira, Cristina M.; Guignabert, Christophe; Bekker, Janine M.; Schellong, Stefan; Urashima, Takashi; Wang, Lingli; Morrell, Nicholas W.; Rabinovitch, Marlene

doi:10.1172/jci32503

Cited by 331 publications

(384 citation statements)

References 56 publications

(66 reference statements)

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“…HPAECs were seeded onto 10cm tissue culture dishes at 5x10 Furthermore, vascular cells from IPAH patients are known to maintain a proliferative phenotype in vitro [31][32][33]. These results are consistent with previous findings demonstrating that IL-33 expression is known to be inversely related to cellular proliferation.…”

Section: Chromatin Immunoprecipitaion (Chip) Analysissupporting

confidence: 90%

Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

Shao

Perros

Caramori

et al. 2014

Biochemical and Biophysical Research Communications

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Section: Chromatin Immunoprecipitaion (Chip) Analysissupporting

confidence: 90%

Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

Shao

Perros

Caramori

et al. 2014

Biochemical and Biophysical Research Communications

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“…An indicator of RV contractility, RV dP/dt max measured during RV catheterization was significantly increased after 3 weeks of hypoxia in SuHx mice compared with both baseline and VehHx controls and increased in parallel with RVSP and hypertrophy. The latter phenomenon has been observed in several mouse PH studies 10,12,14 and represents increased contractility in the hypertensive and hypertrophic RV. 14 RV dP/dt max returned to normoxic values after 10 weeks of recovery from chronic hypoxia (Fig.…”

Section: Rv Dimension and Systolic Functionmentioning

confidence: 53%

The Sugen 5416/Hypoxia Mouse Model of Pulmonary Hypertension Revisited: Long‐Term Follow‐Up

et al. 2014

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a SHV and GH contributed equally to this work.Abstract: The combination of a vascular endothelial growth factor receptor antagonist, Sugen 5416 (SU5416), and chronic hypoxia is known to cause pronounced pulmonary hypertension (PH) with angioobliterative lesions in rats and leads to exaggerated PH in mice as well. We sought to determine whether weekly SU5416 injections during 3 weeks of hypoxia leads to long-term development of angioobliterative lesions and sustained or progressive PH in mice. Male C57BL/6J mice were injected with SU5416 (SuHx) or vehicle (VehHx) weekly during 3 weeks of exposure to 10% oxygen. Echocardiographic and invasive measures of hemodynamics and pulmonary vascular morphometry were performed after the 3-week hypoxic exposure and after 10 weeks of recovery in normoxia. SuHx led to higher right ventricular (RV) systolic pressure and RV hypertrophy than VehHx after 3 weeks of hypoxia. Ten weeks after hypoxic exposure, RV systolic pressure decreased but remained elevated in SuHx mice compared with VehHx or normoxic control mice, but RV hypertrophy had resolved. After 3 weeks of hypoxia and 10 weeks of followup in normoxia, tricuspid annular plane systolic excursion was significantly decreased, indicating decreased systolic RV function. Very few angioobliterative lesions were found at the 10-week follow-up time point in SuHx mouse lungs. In conclusion, SU5416 combined with 3 weeks of hypoxia causes a more profound PH phenotype in mice than hypoxia alone. PH persists over 10 weeks of normoxic follow-up in SuHx mice, but significant angioobliterative lesions do not occur, and neither PH nor RV dysfunction worsens. The SuHx mouse model is a useful adjunct to other PH models, but the search will continue for a mouse model that better recapitulates the human phenotype.

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“…In addition to eNOS, recent studies demonstrate the involvement of Wnt/␤-catenin signaling in BMP-2 stimulated PAEC migration, which in the healthy pulmonary endothelium is mediated by BMPRII (28,29). Although there are few studies examining cross-talk between NO and Wnt/␤-catenin signaling, there is some evidence of it in the literature.…”

Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein Receptor II Is a Novel Mediator of Endothelial Nitric-oxide Synthase Activation

Gangopahyay

Oran

Bauer

et al. 2011

Journal of Biological Chemistry

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Activation of bone morphogenetic protein (BMP) receptor II (BMPRII) promotes pulmonary artery endothelial cell (PAEC) survival, proliferation, and migration. Mutations to BMPRII are associated with the development of pulmonary arterial hypertension (PAH). Endothelial dysfunction, including decreased endothelial nitric-oxide synthase (eNOS) activity and loss of bioactive nitric oxide (NO), plays a prominent role in the development of PAH. We hypothesized that stimulation of BMPRII promotes normal PAEC function by activating eNOS. We report that BMPRII ligands, BMP2 and BMP4, (i) stimulate eNOS phosphorylation at a critical regulatory site, (ii) increase eNOS activity, and (iii) result in canonical changes in eNOS proteinprotein interactions. The stimulation of eNOS activity by BMPRII ligands was largely dependent on protein kinase A (PKA) activation, as demonstrated using the PKA inhibitors H89 and myristoylated PKI(6 -22) amide. PAEC migration stimulated by BMP2 and BMP4 was inhibited by the NOS inhibitor L-nitroarginine methyl ester, providing functional evidence of eNOS activation. Furthermore, BMP2 and BMP4 failed to stimulate eNOS phosphorylation when BMPRII was knocked down by siRNA. Most important to the pathophysiology of the disease, BMP2 and BMP4 failed to stimulate eNOS phosphorylation in PAECs isolated from patients with mutations in the BMPR2 gene. These data demonstrate a new action of BMPs/ BMPRII in the pulmonary endothelium and provide novel mechanistic insight into the pathogenesis of PAH. Pulmonary arterial hypertension (PAH)2 is a devastating disease, characterized by increasing pulmonary arterial pressures, leading to right heart failure and eventually, death (1, 2). Recent studies demonstrate an important role for BMPRII in the pathogenesis of the disease when mutations to the BMPR2 gene were identified as a major underlying cause of heritable or familial PAH (FPAH) (3-5). Approximately 144 different mutations in 210 patients with FPAH have now been identified (6 -8). Additionally, it is estimated that 20% of patients with idiopathic PAH (IPAH) harbor mutations to the BMPR2 gene. These mutations may be a previously undetected inherited mutation or arise from sporadic mutation of the gene.BMPRII is widely expressed in normal tissues. In the lung vasculature, BMPRII is most highly expressed on endothelial cells (9) and at lower levels in smooth muscle cells and fibroblasts. Expression of BMPRII is markedly reduced in the pulmonary vasculature of patients with FPAH and IPAH, regardless of whether they harbor mutations in the BMPR2 gene (9).Pulmonary artery smooth muscle cells (PASMCs) from patients with mutations in BMPRII have a reduced capacity to activate Smad1/5. This is coupled with a reduced ability of BMPs to inhibit proliferation of PASMCs (10). In contrast, the BMPRII ligands BMP2 and BMP4 promote proliferation, migration, and survival in PAECs (11, 12). The opposite effects of BMPs on PAECs and PASMCs provide a convincing model for pulmonary vascular damage in PAH, where a loss of BMP...

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An antiproliferative BMP-2/PPARγ/apoE axis in human and murine SMCs and its role in pulmonary hypertension

Cited by 331 publications

References 56 publications

Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

The Sugen 5416/Hypoxia Mouse Model of Pulmonary Hypertension Revisited: Long‐Term Follow‐Up

Bone Morphogenetic Protein Receptor II Is a Novel Mediator of Endothelial Nitric-oxide Synthase Activation

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