This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 102/3/380    most recent CIRCRESAHA.107.161059v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by El-Bizri, N. Articles by Rabinovitch, M. Search for Related Content PubMed PubMed Citation Articles by El-Bizri, N. Articles by Rabinovitch, M. Related Collections Remodeling Apoptosis Genetically altered mice Pulmonary biology and circulation Smooth muscle proliferation and differentiation Pulmonary circulation and disease

(Circulation Research. 2008;102:380.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Smooth Muscle Protein 22–Mediated Patchy Deletion of Bmpr1a Impairs Cardiac Contractility but Protects Against Pulmonary Vascular Remodeling

Nesrine El-Bizri, Lingli Wang, Sandra L. Merklinger, Christophe Guignabert, Tushar Desai, Takashi Urashima, Ahmad Y. Sheikh, Russell H. Knutsen, Robert P. Mecham, Yuji Mishina, Marlene Rabinovitch

From the Cardiopulmonary Research Program (N.E.-B., L.W., S.L.M., C.G., M.R.), Vera Moulton Wall Center for Pulmonary Vascular Disease; Departments of Pediatrics (N.E.-B., L.W., S.L.M., C.G., T.U. M.R.), Biochemistry (T.D.), Pulmonary and Critical Care Medicine (T.D.), and Cardiothoracic Surgery (A.Y.S.), Stanford University School of Medicine, Calif; Department of Cell Biology (R.H.K., R.P.M.), Washington University School of Medicine, St Louis, Mo; and Molecular Developmental Biology Group (Y.M.), Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC.

Correspondence to Marlene Rabinovitch, MD, Stanford University School of Medicine, CCSR-2245B, 269 Campus Dr, Stanford, CA 94305-5162. E-mail marlener{at}stanford.edu

Vascular expression of bone morphogenetic type IA receptor (Bmpr1a) is reduced in lungs of patients with pulmonary arterial hypertension, but the significance of this observation is poorly understood. To elucidate the role of Bmpr1a in the vascular pathology of pulmonary arterial hypertension and associated right ventricular (RV) dysfunction, we deleted Bmpr1a in vascular smooth muscle cells and in cardiac myocytes in mice using the SM22;TRE-Cre/LoxP;R26R system. The LacZ distribution reflected patchy deletion of Bmpr1a in the lung vessels, aorta, and heart of SM22;TRE-Cre;R26R;Bmpr1a^flox/+ and flox/flox mutants. This reduction in BMPR-IA expression was confirmed by Western immunoblot and immunohistochemistry in the flox/flox group. This did not affect pulmonary vasoreactivity to acute hypoxia (10% O₂) or the increase in RV systolic pressure and RV hypertrophy following 3 weeks in chronic hypoxia. However, both SM22;TRE-Cre;R26R;Bmpr1a^flox/+ and flox/flox mutant mice had fewer muscularized distal pulmonary arteries and attenuated loss of peripheral pulmonary arteries compared with age-matched control littermates in hypoxia. When Bmpr1a expression was reduced by short interference RNA in cultured pulmonary arterial smooth muscle cells, serum-induced proliferation was attenuated explaining decreased hypoxia-mediated muscularization of distal vessels. When Bmpr1a was reduced in cultured microvascular pericytes by short interference RNA, resistance to apoptosis was observed and this could account for protection against hypoxia-mediated vessel loss. The similar elevation in RV systolic pressure and RV hypertrophy, despite the attenuated remodeling with chronic hypoxia in the flox/flox mutants versus controls, was not a function of elevated left ventricular end diastolic pressure but was associated with increased periadventitial deposition of elastin and collagen, potentially influencing vascular stiffness.

Key Words: Bmpr1a (Alk3) • pulmonary hypertension • hypoxia • smooth muscle cell • pericyte • transgenic mice

This article has been cited by other articles:

				C. Guignabert, C. M. Alvira, T.-P. Alastalo, H. Sawada, G. Hansmann, M. Zhao, L. Wang, N. El-Bizri, and M. Rabinovitch Tie2-mediated loss of peroxisome proliferator-activated receptor-{gamma} in mice causes PDGF receptor-{beta}-dependent pulmonary arterial muscularization Am J Physiol Lung Cell Mol Physiol, December 1, 2009; 297(6): L1082 - L1090. [Abstract] [Full Text] [PDF]

				A. Shifren, A. G. Durmowicz, R. H. Knutsen, G. Faury, and R. P. Mecham Elastin insufficiency predisposes to elevated pulmonary circulatory pressures through changes in elastic artery structure J Appl Physiol, November 1, 2008; 105(5): 1610 - 1619. [Abstract] [Full Text] [PDF]

				N. El-Bizri, C. Guignabert, L. Wang, A. Cheng, K. Stankunas, C.-P. Chang, Y. Mishina, and M. Rabinovitch SM22{alpha}-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development, and influences organogenesis Development, September 1, 2008; 135(17): 2981 - 2991. [Abstract] [Full Text] [PDF]