cyclin-d1 and Hemorrhage

Mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase Shp2, cause Noonan syndrome and LEOPARD syndrome, inherited multifaceted diseases including cardiac and vascular defects. However, the function of Shp2 in blood vessels, especially in vascular smooth muscle cells (VSMCs), remains largely unknown. We generated mice in which Shp2 was specifically deleted in VSMCs and embryonic cardiomyocytes using the SM22α-Cre transgenic mouse line. Conditional Shp2 knockout resulted in massive hemorrhage, cardiovascular defects and embryonic lethality at the late embryonic developmental stage (embryonic date 16.5). The thinning of artery walls in Shp2-knockout embryos was due to decreased VSMC number and reduced extracellular matrix deposition. Myocyte proliferation was decreased in Shp2-knockout arteries and hearts. Importantly, cardiomyocyte-specific Shp2-knockout did not cause similar vascular defects. Shp2 was required for TGFβ1-induced expression of ECM components, including collagens in VSMCs. In addition, collagens were sufficient to promote Shp2-inefficient VSMC proliferation. Finally, Shp2 was deleted in adult mouse VSMCs by using SMMHC-CreER

Topics: Animals; Carotid Arteries; Cell Proliferation; Collagen; Cyclin D1; Embryo, Mammalian; Extracellular Matrix; Female; Heart; Hemorrhage; Integrases; Male; Mice, Knockout; Muscle, Smooth, Vascular; Myocardium; Myocytes, Smooth Muscle; Neointima; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Rats; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta