SM22alpha-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development, and influences organogenesis.
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 SM22alpha-Cre mice. SM22alpha-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, SM22alpha-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. SM22alpha-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 SM22alpha-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.
El-Bizri
Nesrine
N
Cardiopulmonary Research Program, Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, California, CA, USA.
Guignabert
Christophe
C
Wang
Lingli
L
Cheng
Alexander
A
Stankunas
Kryn
K
Chang
Ching-Pin
CP
Mishina
Yuji
Y
Rabinovitch
Marlene
M
D000818:Animals; D017209:Apoptosis; D001808:Blood Vessels / Q000196:embryology* / Q000201:enzymology; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000172:deficiency*; D001921:Brain / Q000002:abnormalities / Q000098:blood supply / Q000196:embryology; D002465:Cell Movement; D049109:Cell Proliferation; D020964:Embryo Loss; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000201:enzymology / Q000473:pathology; D017353:Gene Deletion; D006321:Heart / Q000196:embryology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000473:pathology; D038081:Organogenesis; D020286:Pericytes / Q000166:cytology / Q000201:enzymology
D008840:Microfilament Proteins; D009124:Muscle Proteins; C051615:transgelin; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; C045073:Cre recombinase; D019426:Integrases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9