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

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Besnier, Marie | Galaup, Ariane | Henry, Jean-Paul | Coquerel, David | Gueret, Alexandre | Mulder, Paul | Brakenhielm, Ebba | Thuillez, Christian | Germain, Stéphane | Richard, Vincent | Ouvrard-Pascaud, Antoine

Edité par CCSD ; Federation of American Society of Experimental Biology -

International audience. 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 ven-tricular (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 dissocia-tion of endothelial VEGFR2/VE-cadherin), together with higher infiltration of proangiogenic M2 macro-phages 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 endo-thelial 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 m) were likely to participate in increased LV perfu-sion 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 di-astolic function 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

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