Besnier Marie, Galaup Ariane, Nicol Lionel, Henry Jean-Paul, Coquerel David, Gueret Alexandre, Mulder Paul, Brakenhielm Ebba, Thuillez Christian, Germain Stéphane, Richard Vincent, Ouvrard-Pascaud Antoine
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and.
INSERM U1050, Center for Interdisciplinary Research in Biology, Collège de France, Paris, France.
FASEB J. 2014 Aug;28(8):3351-61. doi: 10.1096/fj.13-245753. Epub 2014 Apr 23.
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.
蛋白酪氨酸磷酸酶1B（PTP1B）可调节酪氨酸激酶受体，其中包括血管内皮生长因子受体2（VEGFR2），它是血管生成的关键组成部分。由于小鼠中PTP1B缺乏可在心肌梗死（MI）后2个月改善左心室（LV）功能，我们推测MI后早期通过激活VEGFR2增强血管生成有助于这种改善。MI后3天，PTP1B（-/-）小鼠梗死边界处的毛细血管密度增加[+7±2% vs. 野生型（WT），P = 0.05]。这与细胞外信号调节激酶2磷酸化增加和VEGFR2激活（即磷酸化-Src/Src/VEGFR2以及内皮VEGFR2/血管内皮钙黏蛋白解离）相关，同时促血管生成的M2巨噬细胞浸润增加，而总体浸润不变。在体外，我们表明使用RNA干扰抑制或沉默PTP1B可增加VEGF诱导的小鼠心脏微血管内皮细胞迁移和增殖以及成纤维细胞生长因子（FGF）诱导的大鼠主动脉平滑肌细胞增殖。在PTP1B（-/-）小鼠MI后8天，LV毛细血管密度增加（+21±3% vs. WT；P<0.05），小直径动脉数量增加（15 - 50μm），这可能参与了通过磁共振成像评估的LV灌注增加以及LV顺应性改善，表明舒张功能障碍减轻。总之，PTP1B缺乏通过增强血管生成、心肌灌注和舒张功能，在缺血后迅速减轻MI诱导的心力衰竭。
