Herkenne Stéphanie, Paques Cécile, Nivelles Olivier, Lion Michelle, Bajou Khalid, Pollenus Thomas, Fontaine Marie, Carmeliet Peter, Martial Joseph A, Nguyen Ngoc-Quynh-Nhu, Struman Ingrid
Molecular Angiogenesis Laboratory, GIGA Research, University of Liège, Avenue de l'Hôpital, 1, 4000 Liège, Belgium. Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy. Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy.
Molecular Angiogenesis Laboratory, GIGA Research, University of Liège, Avenue de l'Hôpital, 1, 4000 Liège, Belgium.
Sci Signal. 2015 Nov 17;8(403):ra117. doi: 10.1126/scisignal.aaa2403.
In endothelial cells, binding of vascular endothelial growth factor (VEGF) to the receptor VEGFR2 activates multiple signaling pathways that trigger processes such as proliferation, survival, and migration that are necessary for angiogenesis. VEGF-bound VEGFR2 becomes internalized, which is a key step in the proangiogenic signal. We showed that the urokinase plasminogen activator receptor (uPAR) interacted with VEGFR2 and described the mechanism by which this interaction mediated VEGF signaling and promoted angiogenesis. Knockdown of uPAR in human umbilical vein endothelial cells (HUVECs) impaired VEGFR2 signaling, and uPAR deficiency in mice prevented VEGF-induced angiogenesis. Upon exposure of HUVECs to VEGF, uPAR recruited the low-density lipoprotein receptor-related protein 1 (LRP-1) to VEGFR2, which induced VEGFR2 internalization. Thus, the uPAR-VEGFR2 interaction is crucial for VEGF signaling in endothelial cells.
在内皮细胞中，血管内皮生长因子（VEGF）与受体VEGFR2结合会激活多种信号通路，这些信号通路会触发诸如增殖、存活和迁移等血管生成所必需的过程。与VEGF结合的VEGFR2会发生内化，这是促血管生成信号中的关键步骤。我们发现尿激酶型纤溶酶原激活物受体（uPAR）与VEGFR2相互作用，并描述了这种相互作用介导VEGF信号传导和促进血管生成的机制。在人脐静脉内皮细胞（HUVECs）中敲低uPAR会损害VEGFR2信号传导，而小鼠中的uPAR缺陷会阻止VEGF诱导的血管生成。当HUVECs暴露于VEGF时，uPAR会将低密度脂蛋白受体相关蛋白1（LRP-1）募集到VEGFR2，从而诱导VEGFR2内化。因此，uPAR-VEGFR2相互作用对于内皮细胞中的VEGF信号传导至关重要。
