Abstract 1246: Conditional Deletion of the BMP Type II Receptor Reveals Multiple Tissue-Specific Roles in Cardiovascular Development
BACKGROUND: Bone morphogenetic proteins (BMPs) play critical roles during embryogenesis and in the pathogenesis of cardiopulmonary disease. Heterozygous germline mutations of the BMP type II receptor (BMPRII) are associated with pulmonary arterial hypertension and congenital heart defects. BMPRII is expressed in multiple cell types. However, mice with homozygous deletion of BMPRII exhibit early embryonic lethality, so that the function of BMPRII in specific cell types in vivo remains unknown.
METHODS: The BMPRII gene was disrupted in vivo using the Cre-loxP system. Cre transgenic mice were used to achieve global deletion (Mox2-Cre) or tissue-specific deletion in the lineage of endothelial/endocardial cells (Tie2-Cre), smooth muscle cells (SM22alpha-Cre), neural crest-derived cells (Wnt1-Cre), and cardiac myocytes (alphaMHC-Cre). Cardiovascular defects of the mutant mice were analyzed.
RESULTS: Embryos with deletion of BMPRII using Mox2-Cre survived until mid-to-late gestation (E14.5–18.5), but exhibited severe cardiac defects including double outlet right ventricle (DORV), ventricular septal defect (VSD), and abnormal atrioventricular cushion (AVC) remodeling, suggesting critical roles of BMPRII in both outflow tract (OFT) and inflow tract (IFT) development. Interestingly, there were no obvious defects observed in the mutant mice with alphaMHC-Cre, indicating the functional redundancy of BMPRII with other type II receptors in the myocardium. The IFT and AVC defects (membranous VSD, ASD, and thickened valves) were also detected in mutant mice expressing Tie2-Cre, which died within one week after birth. Endocardial BMPRII may therefore regulate growth and remodeling of mesenchymal cells in the AVC. Abnormal positioning of the OFT (ascending aorta) was observed following deletion with either Wnt1-Cre or SM22alpha-Cre, indicating that BMPRII in neural crest-derived smooth muscle cells and mesenchymal cells is required for the appropriate positioning and/or rotation of the OFT.
CONCLUSIONS: Conditional deletion of BMPRII has identified multiple cell type-specific roles in cardiovascular development. BMPRII is required for normal positioning of OFT and AVC remodeling, but not for myocardial development.