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

INTRODUCTION Bone morphogenetic protein receptors (BMPRs) are members of the transforming growth factor β superfamily of receptors (de Caestecker, 2004; Mehra and Wrana, 2002). Heteromeric complexes form between BMPR1 and BMPR2 (Gilboa et al., 2000). Aberrant BMP signaling has been linked to pulmonary arterial hypertension (PAH). Various germline mutations in BMPR2 have been identified in familial and even sporadic forms of the disease (Deng et al., 2000; Lane et al., 2000; Thomson et al., 2001). Moreover, independent of a mutation, expression of BMPR2 (Atkinson et al., 2002) and BMPR1A (Du et al., 2003) is reduced in lungs of PAH patients. PAH is a potentially fatal disease (Abenhaim et al., 1996) characterized by both obliteration of proximal pulmonary arteries resulting from vascular smooth muscle cell (VSMC) proliferation and migration (Jeffery and Morrell, 2002), and loss of distal arteries associated with endothelial cell (EC) (Campbell et al., 2001) and pericyte apoptosis (Zhao et al., 2003). These pathological features account for the progressive increase in pulmonary vascular resistance culminating in right-side heart failure (Humbert et al., 2004; Rubin, 1997). Mice homozygous null for Bmpr2 (Beppu et al., 2000), Bmpr1a (Mishina et al., 1995), the ligand Bmp4 (Winnier et al., 1995) and the effector Smad4 (Sirard et al., 1998) die early in embryonic life owing to a lack of mesodermal induction. In mice with Flk1-targeted deletion of Bmpr1a (Flk1-Cre;Bmpr1aflox/flox) (Flk1 is also known Kdr – Mouse Genome Informatics) (Park et al., 2006), lethality occurs between E10.5 and E11.5, in association with massive abdominal hemorrhage. These mice exhibit dilatation of large vessels owing to poor recruitment of VSMCs around the EC layer, but it is not clear whether the vascular phenotype is due to Bmpr1adeficient ECs or SMCs (Park et al., 2006). In this study, we determined whether VSMC deletion of Bmpr1a could cause abnormalities in vasculogenesis that might explain a propensity to PAH. We bred mice expressing floxed Bmpr1a and ROSA26 with SM22α-Cre mice [SM22α is also known as transgelin (Tagln) – Mouse Genome Informatics]. Progeny homozygous for deletion of Bmpr1a, SM22α-Cre;R26R;Bmpr1a flox/flox, died soon after E11 with massive vascular and pericardial hemorrhage. These mice had a thin ventricular wall and aneurysmal dilatation of large vessels associated with reduced myocyte proliferation related to decreased MMP9 and MMP2 activities. Defective brain development documented in the SM22α-Cre;R26R;Bmpr1aflox/flox mice was associated with impaired clearing of brain microvessels related to a resistance of pericytes to apoptosis and decreased levels of MMP2. SM22α-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development, and influences organogenesis