Shp2 in myocytes is essential for cardiovascular and neointima development.

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 TGFß1-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-CreERT2 and tamoxifen induction. Shp2 deletion dramatically inhibited the expression of ECM components, proliferation of VSMCs and neointima formation in a carotid artery ligation model. Therefore, Shp2 is required for myocyte proliferation in cardiovascular development and vascular remodeling through TGFß1-regulated collagen synthesis.

Low-Protein Diet-Induced Fetal Growth Restriction Leads to Exaggerated Proliferative Response to Vascular Injury in Postnatal Life.

BACKGROUND: We investigated the effects of fetal growth restriction (FGR) induced by maternal protein restriction on inflammatory vascular remodeling using a cuff-induced vascular injury mouse model. METHODS: Dams (C57BL/6J strain mice) were fed an isocaloric diet containing 20% protein (normal protein; NP) or 8% protein (low protein; LP) from 10 weeks of age until delivery. On the day of delivery, all dams were returned to the NP diet. After weaning, offspring were fed the NP diet. When offspring were 10 weeks of age, vascular injury was induced by polyethylene cuff placement around the femoral artery. RESULTS: Birth weight in offspring from dams fed LP until delivery (LPO) was significantly lower, but body weight was the same at 2 weeks after birth compared with that in NP offspring (NPO). Arterial blood pressure at 12 weeks of age did not differ between LPO and NPO. Neointima formation was exaggerated in LPO compared with NPO and associated with an increase in cell proliferation assessed by proliferating cell nuclear antigen (PCNA) staining index. Moreover, LPO showed enhanced expression of monocyte chemotactic protein-1, interleukin (IL)-6, IL-1ß, tumor necrosis factor-α, and production of superoxide anion in the injured artery. Moreover, mRNA expression of isoforms of NAD(P)H oxidase subunits such as p22phox, p40phox, p47phox, p67phox, gp91phpx, and Rac1 in the injured arteries were enhanced in LPO. Furthermore, HIF-1α expression was increased in LPO compared with that in NPO. CONCLUSIONS: These results suggest that maternal low-protein diet-induced FGR increases susceptibility of the vasculature to postnatal injury.