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.

Haibo Wang

Aniket Ramshekar

Eric Kunz

David B. Sacks

M. Elizabeth Hartnett

Angiogenesis

《血管生成》是一本国际同行评审期刊，致力于发表高质量的原创文章和评论，了解在生理和病理条件下调节血管生成的细胞和分子机制。作为代表全方位血管生成研究的快速交流的中心来源，这本多学科期刊发表使用分子、体外、动物模型系统和血管生成疾病临床研究的创新实验研究。血管生成还报道了促进或抑制血管生成的新治疗方法以及疾病诊断和预后的新标志物和技术。

Angiogenesis is an international peer-reviewed journal dedicated to publishing high-quality original research and reviews that explore the cellular and molecular mechanisms regulating angiogenesis under physiological and pathological conditions. As a central source for rapid communication in the field of angiogenesis research, this multidisciplinary journal publishes innovative experimental studies utilizing molecular, in vitro, animal model systems, and clinical research on angiogenesis-related diseases. Angiogenesis also reports on new therapeutic approaches that promote or inhibit angiogenesis, as well as novel biomarkers and techniques for disease diagnosis and prognosis.

《Angiogenesis》是一本国际同行评审期刊，专注于发表高质量的原创研究和评论，探讨在生理和病理条件下调节血管生成的细胞和分子机制。作为血管生成研究的快速交流中心，这本多学科期刊发表基于分子、体外实验、动物模型和临床研究的创新实验成果。《Angiogenesis》还报道了促进或抑制血管生成的新治疗方法，以及疾病诊断和预后的新标志物和技术。

IQGAP1 causes choroidal neovascularization by sustaining VEGFR2-mediated Rac1 activation

A role of IQG AP1 and the interaction between IQGAP1 and Rac1GTP to restore CECs quiescence and, therefore, prevent vision-threatening CNV in nAMD is supported.

Category	Quartile
医学	1
医学, 外周血管病	2

IQGAP1 causes choroidal neovascularization by sustaining VEGFR2-mediated Rac1 activation

ivySCI AI Smartly Parses PDF, Answers Researchers' Questions, and Helps You Understand Papers in Seconds

Journal Info

Category	Quartile
PERIPHERAL VASCULAR DISEASE	1