PTP1b is a physiologic regulator of vascular endothelial growth factor signaling in endothelial cells.
PTP1b is a physiologic regulator of vascular endothelial growth factor signaling in endothelial cells.
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DOI：
10.1161/circulationaha.114.009683
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发表时间：
2014-09-09
期刊：
影响因子：
37.8
通讯作者：
Simons M
中科院分区：
文献类型：
--
作者：
Lanahan AA;Lech D;Dubrac A;Zhang J;Zhuang ZW;Eichmann A;Simons M
血管内皮生长因子受体-2（VEGFR 2）信号的调节是决定血管树形成程度的控制点。最近的研究表明，VEGFR 2内皮细胞运输在控制其活性方面发挥着重要作用，并表明磷酸酪氨酸磷酸酶1b（PTP 1b）参与了这一过程。本研究旨在确定PTP 1b在内皮VEGFR 2信号传导中的作用及其在血管生成和动脉生成调节中的作用。我们产生了携带内皮特异性缺失PTP 1b的小鼠，并在体外和体内研究了这种敲除对VEGF信号传导、血管生成和动脉生成的影响。与对照组相比，PTP 1b基因敲除的内皮细胞增加了VEGF依赖的细胞外信号调节激酶信号传导、出芽、迁移和增殖的激活。内皮细胞PTP 1b缺失小鼠的视网膜和Matrigel植入物血管生成增加，并加速伤口愈合，表明血管生成增强。在后肢缺血小鼠模型中观察到动脉血流恢复更快和大量新形成的小动脉，证明了动脉生成增加。PTP 1b内皮敲除也挽救了synectin敲除小鼠股总动脉结扎后受损的血流恢复。PTP 1b是内皮细胞VEGFR 2信号传导的关键调节因子，在调节血管树形成的程度中起重要作用。
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.