Enhanced angiogenesis and increased cardiac perfusion after myocardial infarction in protein tyrosine phosphatase 1B‐deficient mice

The protein tyrosine phosphatase 1B (PTP1B) modulates tyrosine kinase receptors, among which is the vascular endothelial growth factor receptor type 2 (VEGFR2), a key component of angiogenesis. Because PTP1B deficiency in mice improves left ventricular (LV) function 2 mo after myocardial infarction (MI), we hypothesized that enhanced angiogenesis early after MI via activated VEGFR2 contributes to this improvement. At 3 d after MI, capillary density was increased at the infarct border of PTP1B –/– mice [+ 7±2% vs. wild‐type (WT), P = 0.05]. This was associated with increased extracellular signal‐regulated kinase 2 phosphorylation and VEGFR2 activation (i.e. , phosphorylated‐Src/Src/VEGFR2 and dissociation of endothelial VEGFR2/VE‐cadherin), together with higher infiltration of proangiogenic M2 macrophages within unchanged overall infiltration. In vitro , we showed that PTP1B inhibition or silencing using RNA interference increased VEGF‐induced migration and proliferation of mouse heart microvascular endothelial cells as well as fibroblast growth factor (FGF)‐induced proliferation of rat aortic smooth muscle cells. At 8 d after MI in PTP1B –/– mice, increased LV capillary density (+21 ±3% vs. WT; P <0.05) and an increased number of small diameter arteries (15‐50 μm) were likely to participate in increased LV perfusion assessed by magnetic resonance imaging and improved LV compliance, indicating reduced diastolic dysfunction. In conclusion, PTP1B deficiency reduces MI‐induced heart failure promptly after ischemia by enhancing angiogenesis, myocardial perfusion, and diastolic function.—Besnier, M., Galaup, A., Nicol, L., Henry, J.‐P, Coquerel, D., Gueret, A., Mulder, P., Brakenhielm, E., Thuillez, C., Germain, S., Richard, V., Ouvrard‐Pascaud, A. Enhanced angiogenesis and increased cardiac perfusion after myocardial infarction in protein tyrosine phosphatase 1B‐deficient mice. FASEB J. 28, 3351–3361 (2014). www.fasebj.org