Endothelial deletion of protein tyrosine phosphatase-1B protects against pressure overload-induced heart failure in mice

Aims: Cardiac angiogenesis is an important determinant of heart failure.We examined the hypothesis that protein tyrosine phosphatase (PTP)-1B, a negative regulator of vascular endothelial growth factor (VEGF) receptor-2 activation, is caus- ally involved in the cardiac microvasculature rarefaction during hypertrophy and that deletion of PTP1B in endothelial cells prevents the development of heart failure. Methods: Cardiac hypertrophy was induced by transverse aortic constriction (TAC) in mice with endothelial-specific deletion of and results PTP1B (End.PTP1B-KO) and controls (End.PTP1B-WT). Survival up to 20 weeks after TAC was significantly improved in mice lacking endothelial PTP1B. Serial echocardiography revealed a better systolic pump function, less pronounced cardiac hypertrophy, and left ventricular dilation compared with End.PTP1B-WT controls. Histologically, banded hearts from End.PTP1B-KO mice exhibited increased numbers of PCNA-positive, proliferating endothelial cells resulting in preserved cardiac capillary density and improved perfusion as well as reduced hypoxia, apoptotic cell death, and fibro- sis. Increased relative VEGFR2 and ERK1/2 phosphorylation and greatereNOSexpressionwere present in the hearts of End.PTP1B-KOmice. The absence of PTP1B in endothelial cells also promoted neovascularization following peripheral ischaemia, and bone marrowtransplantation excluded a major contribution of Tie2-positive haematopoietic cells to the improved angiogenesis in End.PTP1B-KOmice. Increased expression of caveolin-1 as well as reducedNADPHoxidase- 4 expression, ROS generation and TGFb signalling were observed and may have mediated the cardioprotective effects of endothelial PTP1B deletion. Conclusions: Endothelial PTP1B deletion improves cardiac VEGF signalling and angiogenesis and protects against chronic afterload- induced heart failure. PTP1B may represent a useful target to preserve cardiac function during hypertrophy.