IQGAP1 causes choroidal neovascularization by sustaining VEGFR2-mediated Rac1 activation
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ORIGINAL PAPER
IQGAP1 causes choroidal neovascularization by sustaining VEGFR2mediated Rac1 activation Haibo Wang1 · Aniket Ramshekar1 · Eric Kunz1 · David B. Sacks2 · M. Elizabeth Hartnett1 Received: 24 April 2020 / Accepted: 1 August 2020 © Springer Nature B.V. 2020
Abstract Loss of visual acuity in neovascular age-related macular degeneration (nAMD) occurs when factors activate choroidal endothelial cells (CECs) to transmigrate the retinal pigment epithelium into the sensory retina and develop into choroidal neovascularization (CNV). Active Rac1 (Rac1GTP) is required for CEC migration and is induced by different AMD-related stresses, including vascular endothelial growth factor (VEGF). Besides its role in pathologic events, Rac1 also plays a role in physiologic functions. Therefore, we were interested in a method to inhibit pathologic activation of Rac1. We addressed the hypothesis that IQGAP1, a scaffold protein with a Rac1 binding domain, regulates pathologic Rac1GTP in CEC migration and CNV. Compared to littermate Iqgap1+/+, Iqgap1−/− mice had reduced volumes of laser-induced CNV and decreased Rac1GTP and phosphorylated VEGFR2 (p-VEGFR2) within lectin-stained CNV. Knockdown of IQGAP1 in CECs significantly reduced VEGF-induced Rac1GTP, mediated through p-VEGFR2, which was necessary for CEC migration. Moreover, sustained activation of Rac1GTP induced by VEGF was eliminated when CECs were transfected with an IQGAP1 construct that is unable to bind Rac1. IQGAP1-mediated Src activation was involved in initiating Rac1 activation, CEC migration, and tube formation. Our findings indicate that CEC IQGAP1 interacts with VEGFR2 to mediate Src activation and subsequent Rac1 activation and CEC migration. In addition, IQGAP1 binding to Rac1GTP results in sustained activation of Rac1, leading to CEC migration toward VEGF. Our study supports a role of IQGAP1 and the interaction between IQGAP1 and Rac1GTP to restore CECs quiescence and, therefore, prevent vision-threatening CNV in nAMD. Keywords Age-related macular degeneration · choroidal neovascularization · IQGAP1 · Vascular endothelial growth factor · Vascular endothelial growth factor receptor 2 · Rac1
Introduction Age-related macular degeneration (AMD) is a leading cause of vision loss worldwide [1]. Loss in visual acuity occurs rapidly in neovascular AMD when various stresses and factors activate choroidal endothelial cells (CECs) and overwhelm homeostatic mechanisms that prevent CEC Electronic supplementary material The online version of this article (doi:https://doi.org/10.1007/s10456-020-09740-y) contains supplementary material, which is available to authorized users. * M. Elizabeth Hartnett [email protected] 1
The John A Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA
Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD 20892, USA
2
transmigration of the retinal pigment epithelium (RPE) [2]. Once in the subretinal space, CECs can proliferate and develop into choroidal n
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