SM22α-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development and influences organogenesis

Nesrine El-Bizri, Christophe Guignabert, Lingli Wang, Alexander Cheng, Kryn Stankunas, Ching Pin Chang, Yuji Mishina, Marlene Rabinovitch

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Expression of bone morphogenetic protein receptor 1A (BMPR1A) is attenuated in the lung vessels of patients with pulmonary arterial hypertension, but the functional impact of this abnormality is unknown. We ablated Bmpr1a in cardiomyocytes and vascular smooth muscle cells (VSMCs) by breeding mice possessing a loxP allele of Bmpr1a (Bmpr1aflox) expressing R26R with SM22α-Cre mice. SM22α-Cre;R26R;Bmpr1aflox/flox mice died soon after embryonic day 11 (E11) with massive vascular and pericardial hemorrhage and impaired brain development. At E10.5, SM22α-Cre;R26R;Bmpr1aflox/flox embryos showed thinning of the myocardium associated with reduced cell proliferation. These embryos also had severe dilatation of the aorta and large vessels with impaired investment of SMCs that was also related to reduced proliferation. SM22α-Cre;R26R;Bmpr1aflox/ flox mice showed collapsed telencephalon in association with impaired clearing of brain microvessels in areas where reduced apoptosis was observed. Transcript and protein levels of matrix metalloproteinase (MMP) 2 and 9 were reduced in E9.5 and E10.5 SM22α-Cre; R26R;Bmpr1aflox/flox embryos, respectively. Knock-down of BMPR1A by RNA interference in human pulmonary artery SMCs reduced MMP2 and MMP9 activity, attenuated serum-induced proliferation, and impaired PDGF-BB-directed migration. RNA interference of MMP2 or MMP9 recapitulated these abnormalities, supporting a functional interaction between BMP signaling and MMP expression. In human brain microvascular pericytes, knock-down of BMPR1A reduced MMP2 activity and knock-down of either BMPR1A or MMP2 caused resistance to apoptosis. Thus, loss of Bmpr1a, by decreasing MMP2 and/or MMP9 activity, can account for vascular dilatation and persistence of brain microvessels, leading to the impaired organogenesis documented in the brain.

Original languageEnglish (US)
Pages (from-to)2981-2991
Number of pages11
JournalDevelopment
Volume135
Issue number17
DOIs
StatePublished - Sep 2008

Keywords

  • Bmpr1a (Alk3)
  • Craniofacial development
  • Heart development
  • MMP2
  • MMP9
  • Matrix metalloproteinase (metallopeptidase)
  • Mouse
  • Pericyte apoptosis
  • SM22α (transgelin, Tagln)
  • Smooth muscle cell proliferation
  • Vasculogenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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  • Cite this

    El-Bizri, N., Guignabert, C., Wang, L., Cheng, A., Stankunas, K., Chang, C. P., Mishina, Y., & Rabinovitch, M. (2008). SM22α-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development and influences organogenesis. Development, 135(17), 2981-2991. https://doi.org/10.1242/dev.017863