Abstract 805: Vascular, Cardiac, and Craniofacial Defects in Mice with Vascular Smooth Muscle Cell-Specific Deletion of Bone Morphogenetic Protein Type IA Receptor (BMPR-IA)
As vascular expression of Bmpr1a is attenuated in lungs of patients with pulmonary arterial hypertension (PAH), we hypothesized that a mouse with selective ablation of Bmpr1a in vascular smooth muscle cells (VSMC) would have abnormal vasculogenesis that could also explain a propensity to PAH. We bred mice expressing floxed Bmpr1a and ROSA26 with SM22a-Cre mice. Whole-mount (WM) LacZ staining confirmed recombination, i.e. Bmpr1a deletion, in heart and vessels. SM22a-Bmpr1a homozygous nulls died at E11 with massive vascular and pericardial hemorrhage. E10.5 mutants showed smaller hearts with thinning of the ventricular myocardium owing to reduced proliferation rather than enhanced apoptosis as judged by PCNA and TUNEL assays respectively. The cardiac defect could be secondary to the extensive vascular defect observed. WM PECAM stained E10.5 mutants showed striking dilation of large vessels and fusion of smaller vessels reminiscent of Smad5 and Alk1 nulls where undifferentiated SMC and elevated expression of proteases were observed. Transverse sections of the mutant dilated aorta revealed thin vessel wall characterized by an extensive endothelial cell (EC) layer surrounded by a single frequently interrupted SMC layer as assessed by PECAM and SM actin staining. An additional vascular defect not previously described, might explain the craniofacial abnormalities that included distorted medial-lateral patterning, collapsed telencephalic vesicles, and compressed hindbrain. We noted impaired clearing of microvessels in vascularized areas in which reduced apoptosis was observed. In conclusion, VSMC expression of Bmpr1a is necessary for normal vasculogenesis that could impact cardiac and craniofacial development. The dilated large vessels and fusion of small vessels may represent impaired VSMC differentiation that results in failure to control EC proliferation and/or enhanced proteolytic activity. Failure to clear craniofacial vessels may represent resistance of pericytes lacking Bmpr1a to apoptosis. The similarity of this mutant to the one lacking Alk1, a gene mutated in Hereditary Hemorrhagic Telangiectasia and implicated in PAH, suggests common effectors of BMP and TGFb signaling necessary for normal vasculogenesis and impaired in PAH.