From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine (A.A.L., D.L., A.D., J.Z., Z.W.Z., A.E., M.S.) and the Department of Cell Biology (M.S.), Yale University School of Medicine, New Haven, CT.
Circulation. 2014 Sep 9;130(11):902-9. doi: 10.1161/CIRCULATIONAHA.114.009683. Epub 2014 Jun 30.
Regulation of vascular endothelial growth factor receptor-2 (VEGFR2) signaling is a control point that determines the extent of vascular tree formation. Recent studies demonstrated an important role played by VEGFR2 endothelial trafficking in control of its activity and suggested the involvement of a phosphotyrosine phosphatase 1b (PTP1b) in this process. This study was designed to define the role of PTP1b in endothelial VEGFR2 signaling and its role in regulation of angiogenesis and arteriogenesis.
We generated mice carrying an endothelial-specific deletion of PTP1b and examined the effect of this knockout on VEGF signaling, angiogenesis, and arteriogenesis in vitro and in vivo. PTP1b knockout endothelial cells had increased VEGF-dependent activation of extracellular signal-regulated kinase signaling, sprouting, migration, and proliferation compared with controls. Endothelial PTP1b null mice had increased retinal and Matrigel implant angiogenesis and accelerated wound healing, pointing to enhanced angiogenesis. Increased arteriogenesis was demonstrated by observations of faster recovery of arterial blood flow and large numbers of newly formed arterioles in the hindlimb ischemia mouse model. PTP1b endothelial knockout also rescued impaired blood flow recovery after common femoral artery ligation in synectin null mice.
PTP1b is a key regulator of endothelial VEGFR2 signaling and plays an important role in regulation of the extent of vascular tree formation.
血管内皮生长因子受体 2（VEGFR2）信号的调节是决定血管树形成程度的一个控制点。最近的研究表明，VEGFR2 内皮细胞运输在控制其活性方面起着重要作用，并提示磷酸酪氨酸磷酸酶 1b（PTP1b）参与了这一过程。本研究旨在确定 PTP1b 在血管内皮 VEGFR2 信号中的作用及其在血管生成和动脉生成中的调节作用。
我们生成了内皮细胞特异性缺失 PTP1b 的小鼠，并研究了这种敲除对 VEGF 信号、体外和体内血管生成和动脉生成的影响。与对照组相比，PTP1b 缺失的内皮细胞具有更高的 VEGF 依赖性细胞外信号调节激酶信号激活、发芽、迁移和增殖。内皮细胞 PTP1b 缺失的小鼠具有更高的视网膜和 Matrigel 植入血管生成和加速伤口愈合，表明血管生成增强。在小鼠后肢缺血模型中观察到动脉血流恢复更快和大量新形成的小动脉，表明动脉生成增加。内皮细胞 PTP1b 缺失也挽救了在联蛋白缺失小鼠中因股总动脉结扎导致的血流恢复受损。
PTP1b 是内皮 VEGFR2 信号的关键调节因子，在调节血管树形成程度方面起着重要作用。
