Lingli Wang, Jan Renier Moonen, Aigin Cao, Sarasa Isobe, Caiyun G. Li, Nancy F. Tojais, Shalina Taylor, David P. Marciano, Pi-I. Chen, Mingxia Xu, Dan Li, Rebecca L. Harper, Nesrine El-Bizri, YuMee Kim, Kryn Stankunas, Marlene Rabinovitch
Stanford University School of Medicine, Howard Hughes Medical Institute, and Lucille Packard Children’s Hospital
United States
Circulation Research
Circ Res 2023;
DOI: 10.1161/CIRCRESAHA.121.320541
Abstract
Objective: Mutations in bone morphogenetic protein receptor 2 (BMPR2) are associated with familial and sporadic pulmonary arterial hypertension (PAH). The functional and molecular link between loss of BMPR2 in pulmonary artery smooth muscle cells (PASMC) and PAH pathogenesis warrants further investigation, as most investigations focus on BMPR2 in pulmonary artery endothelial cells. Determine whether and how decreased BMPR2 is related to the abnormal phenotype of PASMC in PAH.
Methods: SMC-specific Bmpr2-/- mice (BKOSMC) were created and compared to controls in room air, after 3 weeks of hypoxia as a second hit, and following 4 weeks of normoxic recovery. Echocardiography, right ventricular systolic pressure, and right ventricular hypertrophy were assessed as indices of pulmonary hypertension. Proliferation, contractility, gene and protein expression of PASMC from BKOSMC mice, human PASMC with BMPR2 reduced by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation were compared to controls, to investigate the phenotype and underlying mechanism.
Results: BKOSMC mice showed reduced hypoxia-induced vasoconstriction and persistent pulmonary hypertension following recovery from hypoxia, associated with sustained muscularization of distal pulmonary artery. PASMC from mutant compared to control mice displayed reduced contractility at baseline and in response to angiotensin II, increased proliferation and apoptosis resistance. Human PASMC with reduced BMPR2 by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation showed a similar phenotype related to upregulation of phosphorylated extracellular signal related kinase 1/2-pP38-pSMAD2/3 mediating elevation in ARRB2 (β-arrestin2), phosphorylated protein kinase B, and CTNNB1 (β-catenin) and reduction in RHOA and RAC1. Decreasing ARRB2 in PASMC with reduced BMPR2 restored normal signaling, reversed impaired contractility and attenuated heightened proliferation and in mice with inducible loss of BMPR2 in SMC, decreasing ARRB2 prevented persistent pulmonary hypertension.
Conclusions: Agents that neutralize the elevated ARRB2 resulting from loss of BMPR2 in PASMC could prevent or reverse the aberrant hypocontractile and hyperproliferative phenotype of these cells in PAH.
Category
Animal Models of Pulmonary Vascular Disease and Therapy
Genetic Factors Associated with Pulmonary Vascular Disease
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
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