{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:37:44Z","timestamp":1788910664405,"version":"build-2803163510"},"reference-count":96,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T00:00:00Z","timestamp":1631577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY015130"],"award-info":[{"award-number":["R01EY015130"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY017011"],"award-info":[{"award-number":["R01EY017011"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["F30EY032311"],"award-info":[{"award-number":["F30EY032311"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["P30EY014800"],"award-info":[{"award-number":["P30EY014800"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide. Vision loss from the neovascular form is associated with the invasion of choroidal endothelial cells into the neural retina to form vision-threatening macular neovascularization (MNV). Anti-angiogenic agents are the current standard of care but are effective in only ~50% of AMD cases. The molecular mechanisms involved in invasive MNV point to the importance of regulating signaling pathways that lead to pathologic biologic outcomes. In studies testing the effects of AMD-related stresses, activation of the Rho GTPase, Rac1, was found to be important for the choroidal endothelial cell invasion into the neural retina. However, current approaches to prevent Rac1 activation are inefficient and less effective. We summarize active Rac1-mediated mechanisms that regulate choroidal endothelial cell migration. Specifically, we discuss our work regarding the role of a multidomain protein, IQ motif containing GTPase activating protein 1 (IQGAP1), in sustaining pathologic Rac1 activation and a mechanism by which active Rap1, a Ras-like GTPase, may prevent active Rac1-mediated choroidal endothelial cell migration.<\/jats:p>","DOI":"10.3390\/cells10092414","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T03:46:14Z","timestamp":1631591174000},"page":"2414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Regulation of Rac1 Activation in Choroidal Endothelial Cells: Insights into Mechanisms in Age-Related Macular Degeneration"],"prefix":"10.3390","volume":"10","author":[{"given":"Aniket","family":"Ramshekar","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Hartnett","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr, Salt Lake City, UT 84132, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet. Glob. Health."},{"key":"ref_2","first-page":"241","article-title":"Longitudinal Analysis of Retinal Thickness and Retinal Function in Eyes with Large Drusen Secondary to Intermediate Age-Related Macular Degeneration. Ophthalmology","volume":"5","author":"Sassmannshausen","year":"2021","journal-title":"Retin"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1001\/jamaophthalmol.2021.1407","article-title":"Enlargement of Geographic Atrophy From First Diagnosis to End of Life","volume":"139","author":"Colijn","year":"2021","journal-title":"JAMA Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.ophtha.2017.08.038","article-title":"The Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration","volume":"125","author":"Fleckenstein","year":"2018","journal-title":"Ophthalmology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1097\/00006324-200204000-00008","article-title":"Recent advances in the management of age-related macular degeneration","volume":"79","author":"Mittra","year":"2002","journal-title":"Optom. Vis. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1080\/07853890600946724","article-title":"Age-related macular degeneration--emerging pathogenetic and therapeutic concepts","volume":"38","author":"Gehrs","year":"2006","journal-title":"Ann. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ophtha.2007.03.008","article-title":"The natural history and prognosis of neovascular age-related macular degeneration: A systematic review of the literature and meta-analysis","volume":"115","author":"Wong","year":"2008","journal-title":"Ophthalmology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.oret.2019.09.016","article-title":"Type 1 Choroidal Neovascularization Is Associated with Reduced Localized Progression of Atrophy in Age-Related Macular Degeneration","volume":"4","author":"Pfau","year":"2020","journal-title":"Ophthalmol. Retin."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S0002-9394(98)00145-7","article-title":"Clinicopathologic correlations of surgically excised type 1 and type 2 submacular choroidal neovascular membranes","volume":"126","author":"Grossniklaus","year":"1998","journal-title":"Am. J. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1001\/archopht.1988.01060140705039","article-title":"Natural course of poorly defined choroidal neovascularization associated with macular degeneration","volume":"106","author":"Bressler","year":"1988","journal-title":"Arch. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1097\/00006982-199414020-00004","article-title":"Clinicopathologic correlation of choroidal neovascularization demonstrated by indocyanine green angiography in a patient with retention of good vision for almost four years","volume":"14","author":"Chang","year":"1994","journal-title":"Retin"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1016\/S0161-6420(90)32367-9","article-title":"Inactive subretinal neovascularization in age-related macular degeneration","volume":"97","author":"Jalkh","year":"1990","journal-title":"Ophthalmology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/S0161-6420(96)30731-8","article-title":"Characteristics of exudative age-related macular degeneration determined in vivo with confocal and indirect infrared imaging","volume":"103","author":"Hartnett","year":"1996","journal-title":"Ophthalmology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1001\/archopht.1997.01100150347006","article-title":"Occult choroidal neovascularization in age-related macular degeneration. A natural history study","volume":"115","author":"Stevens","year":"1997","journal-title":"Arch. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.ophtha.2019.11.004","article-title":"Consensus Nomenclature for Reporting Neovascular Age-Related Macular Degeneration Data: Consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group","volume":"127","author":"Spaide","year":"2020","journal-title":"Ophthalmology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1001\/archopht.124.7.995","article-title":"Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: The US Twin Study of Age-Related Macular Degeneration","volume":"124","author":"Seddon","year":"2006","journal-title":"Arch. Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.1167\/iovs.14-15841","article-title":"Risk Prediction for Progression of Macular Degeneration: 10 Common and Rare Genetic Variants, Demographic, Environmental, and Macular Covariates","volume":"56","author":"Seddon","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.preteyeres.2013.12.004","article-title":"Nature and nurture- genes and environment- predict onset and progression of macular degeneration","volume":"40","author":"Sobrin","year":"2014","journal-title":"Prog. Retin. Eye. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/ng.3448","article-title":"A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants","volume":"48","author":"Fritsche","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"R174","DOI":"10.1093\/hmg\/ddm212","article-title":"Genetic susceptibility to age-related macular degeneration: A paradigm for dissecting complex disease traits","volume":"16","author":"Swaroop","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_21","first-page":"189","article-title":"Regulation of signaling events involved in the pathophysiology of neovascular AMD","volume":"22","author":"Wang","year":"2016","journal-title":"Mol. Vis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.ophtha.2018.08.035","article-title":"Macular Morphology and Visual Acuity in Year Five of the Comparison of Age-related Macular Degeneration Treatments Trials","volume":"126","author":"Jaffe","year":"2019","journal-title":"Ophthalmology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1161\/01.RES.0000259593.07661.1e","article-title":"Endothelial cell migration during angiogenesis","volume":"100","author":"Lamalice","year":"2007","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1080\/02713680600837408","article-title":"Characterization of barrier properties and inducible VEGF expression of several types of retinal pigment epithelium in medium-term culture","volume":"31","author":"Geisen","year":"2006","journal-title":"Curr. Eye. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.exer.2006.12.012","article-title":"Heterotypic RPE-choroidal endothelial cell contact increases choroidal endothelial cell transmigration via PI 3-kinase and Rac1","volume":"84","author":"Peterson","year":"2007","journal-title":"Exp. Eye. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3316","DOI":"10.1016\/j.ajpath.2015.08.017","article-title":"Rap1 GTPase Inhibits Tumor Necrosis Factor-alpha-Induced Choroidal Endothelial Migration via NADPH Oxidase- and NF-kappaB-Dependent Activation of Rac1","volume":"185","author":"Wang","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.2353\/ajpath.2010.090878","article-title":"The role of vascular endothelial growth factor-induced activation of NADPH oxidase in choroidal endothelial cells and choroidal neovascularization","volume":"177","author":"Hartmann","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1167\/iovs.10-5595","article-title":"The role of RPE cell-associated VEGF(1)(8)(9) in choroidal endothelial cell transmigration across the RPE","volume":"52","author":"Wang","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5525","DOI":"10.1167\/iovs.16-19691","article-title":"Thy-1 Regulates VEGF-Mediated Choroidal Endothelial Cell Activation and Migration: Implications in Neovascular Age-Related Macular Degeneration","volume":"57","author":"Wang","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8271","DOI":"10.1167\/iovs.11-8230","article-title":"Upregulation of CCR3 by age-related stresses promotes choroidal endothelial cell migration via VEGF-dependent and -independent signaling","volume":"52","author":"Wang","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_31","first-page":"e21642","article-title":"Active Rap1-mediated inhibition of choroidal neovascularization requires interactions with IQGAP1 in choroidal endothelial cells","volume":"35","author":"Ramshekar","year":"2021","journal-title":"FASEB. J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s10456-020-09740-y","article-title":"IQGAP1 causes choroidal neovascularization by sustaining VEGFR2-mediated Rac1 activation","volume":"23","author":"Wang","year":"2020","journal-title":"Angiogenesis"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/s10456-021-09770-0","article-title":"7-ketocholesterol induces endothelial-mesenchymal transition and promotes fibrosis: Implications in neovascular age-related macular degeneration and treatment","volume":"24","author":"Wang","year":"2021","journal-title":"Angiogenesis"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3299","DOI":"10.1111\/febs.14985","article-title":"C-type lectin domain group 14 proteins in vascular biology, cancer and inflammation","volume":"286","author":"Khan","year":"2019","journal-title":"FEBS J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1002\/jcp.25689","article-title":"CD93 as a Potential Target in Neovascular Age-Related Macular Degeneration","volume":"232","author":"Tosi","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1167\/iovs.61.8.30","article-title":"The Binding of CD93 to Multimerin-2 Promotes Choroidal Neovascularization","volume":"61","author":"Tosi","year":"2020","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.matbio.2021.05.006","article-title":"The C-type lectin CD93 controls endothelial cell migration via activation of the Rho family of small GTPases","volume":"99","author":"Barbera","year":"2021","journal-title":"Matrix. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"108","DOI":"10.4161\/cam.27599","article-title":"Rho GAPs and GEFs: Controling switches in endothelial cell adhesion","volume":"8","author":"Geerts","year":"2014","journal-title":"Cell. Adh. Migr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.vph.2015.10.003","article-title":"Endothelial RhoGEFs: A systematic analysis of their expression profiles in VEGF-stimulated and tumor endothelial cells","volume":"74","year":"2015","journal-title":"Vasc. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3285","DOI":"10.1016\/j.yexcr.2007.05.027","article-title":"VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2","volume":"313","author":"Garrett","year":"2007","journal-title":"Exp. Cell. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1161\/CIRCRESAHA.109.213983","article-title":"The Rac1 regulator ELMO1 controls vascular morphogenesis in zebrafish","volume":"107","author":"Epting","year":"2010","journal-title":"Circ. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1161\/CIRCRESAHA.110.223388","article-title":"DOCK180 is a Rac activator that regulates cardiovascular development by acting downstream of CXCR4","volume":"107","author":"Sanematsu","year":"2010","journal-title":"Circ. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"24111","DOI":"10.1038\/srep24111","article-title":"PTP1B inhibitor promotes endothelial cell motility by activating the DOCK180\/Rac1 pathway","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s10456-021-09768-8","article-title":"The DOCK protein family in vascular development and disease","volume":"24","author":"Benson","year":"2021","journal-title":"Angiogenesis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"17963","DOI":"10.1074\/jbc.M311721200","article-title":"p68RacGAP is a novel GTPase-activating protein that interacts with vascular endothelial zinc finger-1 and modulates endothelial cell capillary formation","volume":"279","author":"Aitsebaomo","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"12212","DOI":"10.1073\/pnas.0404631101","article-title":"A vascular cell-restricted RhoGAP, p73RhoGAP, is a key regulator of angiogenesis","volume":"101","author":"Su","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.tcb.2005.05.001","article-title":"GDIs: Central regulatory molecules in Rho GTPase activation","volume":"15","author":"DerMardirossian","year":"2005","journal-title":"Trends. Cell. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/72392","article-title":"The Rac-RhoGDI complex and the structural basis for the regulation of Rho proteins by RhoGDI","volume":"7","author":"Scheffzek","year":"2000","journal-title":"Nat. Struct. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Majolee, J., Podieh, F., Hordijk, P.L., and Kovacevic, I. (2021). The interplay of Rac1 activity, ubiquitination and GDI binding and its consequences for endothelial cell spreading. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0254386"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1158\/1535-7163.MCT-13-0164","article-title":"RAC1: An emerging therapeutic option for targeting cancer angiogenesis and metastasis","volume":"12","author":"Bid","year":"2013","journal-title":"Mol. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/nrc1093","article-title":"Tumorigenesis and the angiogenic switch","volume":"3","author":"Bergers","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/S0076-6879(06)06043-5","article-title":"Rational design and applications of a Rac GTPase-specific small molecule inhibitor","volume":"406","author":"Akbar","year":"2006","journal-title":"Methods Enzym."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10007","DOI":"10.1021\/bi010288k","article-title":"Crystal structure of the Rac1-RhoGDI complex involved in nadph oxidase activation","volume":"40","author":"Grizot","year":"2001","journal-title":"Biochemistry"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/367040a0","article-title":"A brain serine\/threonine protein kinase activated by Cdc42 and Rac1","volume":"367","author":"Manser","year":"1994","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0960-9822(06)00052-2","article-title":"Activation of Pak by membrane localization mediated by an SH3 domain from the adaptor protein Nck","volume":"7","author":"Lu","year":"1997","journal-title":"Curr. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1161\/01.RES.0000014227.76102.5D","article-title":"A dominant-negative p65 PAK peptide inhibits angiogenesis","volume":"90","author":"Kiosses","year":"2002","journal-title":"Circ. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"46621","DOI":"10.1074\/jbc.M408877200","article-title":"p21-activated kinase regulates endothelial permeability through modulation of contractility","volume":"279","author":"Stockton","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S1097-2765(01)00428-2","article-title":"Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1","volume":"9","author":"Parrini","year":"2002","journal-title":"Mol. Cell."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S0092-8674(00)00043-X","article-title":"Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch","volume":"102","author":"Lei","year":"2000","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/cmi.2014.89","article-title":"NADPH oxidases: An overview from structure to innate immunity-associated pathologies","volume":"12","author":"Panday","year":"2015","journal-title":"Cell. Mol. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1080\/15216540051080976","article-title":"The NADPH oxidase of endothelial cells","volume":"50","author":"Babior","year":"2000","journal-title":"IUBMB Life"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"R1014","DOI":"10.1152\/ajpregu.00124.2004","article-title":"Endothelial cell superoxide generation: Regulation and relevance for cardiovascular pathophysiology","volume":"287","author":"Li","year":"2004","journal-title":"Am J Physiol Regul Integr Comp. Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Wang, H., and Hartnett, M.E. (2017). Roles of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase in Angiogenesis: Isoform-Specific Effects. Antioxidants, 6.","DOI":"10.3390\/antiox6020040"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1038\/nprot.2013.135","article-title":"Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice","volume":"8","author":"Lambert","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1161\/01.CIR.0000164261.62586.14","article-title":"Role of gp91phox (Nox2)-containing NAD(P)H oxidase in angiogenesis in response to hindlimb ischemia","volume":"111","author":"Tojo","year":"2005","journal-title":"Circ"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1161\/CIRCRESAHA.108.176230","article-title":"Role of nox2-based NADPH oxidase in bone marrow and progenitor cell function involved in neovascularization induced by hindlimb ischemia","volume":"103","author":"Urao","year":"2008","journal-title":"Circ. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/j.kint.2015.09.006","article-title":"Glomerular endothelial cell IQGAP2 and filtration barrier function","volume":"89","author":"Dong","year":"2016","journal-title":"Kidney. Int."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"427","DOI":"10.15252\/embr.201439834","article-title":"The biology of IQGAP proteins: Beyond the cytoskeleton","volume":"16","author":"Hedman","year":"2015","journal-title":"EMBO Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.molimm.2015.02.012","article-title":"IQGAP1: Insights into the function of a molecular puppeteer","volume":"65","author":"Abel","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1161\/01.RES.0000136522.58649.60","article-title":"IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species--dependent endothelial migration and proliferation","volume":"95","author":"Hilenski","year":"2004","journal-title":"Circ. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1161\/01.ATV.0000187472.55437.af","article-title":"IQGAP1 regulates reactive oxygen species-dependent endothelial cell migration through interacting with Nox2","volume":"25","author":"Ikeda","year":"2005","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Berdyshev, E.V., Gorshkova, I., Usatyuk, P., Kalari, S., Zhao, Y., Pyne, N.J., Pyne, S., Sabbadini, R.A., Garcia, J.G., and Natarajan, V. (2011). Intracellular S1P generation is essential for S1P-induced motility of human lung endothelial cells: Role of sphingosine kinase 1 and S1P lyase. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016571"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"23363","DOI":"10.1074\/jbc.271.38.23363","article-title":"Identification of IQGAP as a putative target for the small GTPases, Cdc42 and Rac1","volume":"271","author":"Kuroda","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1002\/j.1460-2075.1996.tb00663.x","article-title":"IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs","volume":"15","author":"Hart","year":"1996","journal-title":"EMBO J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"14857","DOI":"10.1074\/jbc.M808974200","article-title":"Crystal structure of the GTPase-activating protein-related domain from IQGAP1","volume":"284","author":"Kurella","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"20517","DOI":"10.1016\/S0021-9258(17)32023-9","article-title":"Identification of a human rasGAP-related protein containing calmodulin-binding motifs","volume":"269","author":"Weissbach","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0006-291X(03)00759-9","article-title":"Identification and characterization of the Cdc42-binding site of IQGAP1","volume":"305","author":"Mataraza","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nm.3165","article-title":"IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors","volume":"19","author":"Jameson","year":"2013","journal-title":"Nat. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"12324","DOI":"10.1074\/jbc.M109535200","article-title":"The mechanism for regulation of the F-actin binding activity of IQGAP1 by calcium\/calmodulin","volume":"277","author":"Mateer","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.cellsig.2011.12.005","article-title":"IQGAP1 and its binding proteins control diverse biological functions","volume":"24","author":"White","year":"2012","journal-title":"Cell. Signal."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"28183","DOI":"10.1074\/jbc.272.45.28183","article-title":"Calmodulin activates phosphatidylinositol 3-kinase","volume":"272","author":"Joyal","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1074\/jbc.274.1.464","article-title":"IQGAP1 integrates Ca2+\/calmodulin and Cdc42 signaling","volume":"274","author":"Ho","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.bbamem.2008.12.010","article-title":"Cell-cell junction formation: The role of Rap1 and Rap1 guanine nucleotide exchange factors","volume":"1788","author":"Pannekoek","year":"2009","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_84","first-page":"369","article-title":"Rap1 signalling: Adhering to new models. Nature reviews","volume":"2","author":"Bos","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"100","DOI":"10.4161\/cam.27352","article-title":"Rap1 signaling in endothelial barrier control","volume":"8","author":"Pannekoek","year":"2014","journal-title":"Cell. Adh. Migr."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"11675","DOI":"10.1074\/jbc.M412595200","article-title":"Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function","volume":"280","author":"Wittchen","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1074\/jbc.M117.815381","article-title":"The EPAC-Rap1 pathway prevents and reverses cytokine-induced retinal vascular permeability","volume":"293","author":"Ramos","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Wittchen, E.S., Nishimura, E., McCloskey, M., Wang, H., Quilliam, L.A., Chrzanowska-Wodnicka, M., and Hartnett, M.E. (2013). Rap1 GTPase Activation and Barrier Enhancement in RPE Inhibits Choroidal Neovascularization In Vivo. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073070"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1080\/02713683.2018.1454477","article-title":"Activation of the Small GTPase Rap1 Inhibits Choroidal Neovascularization by Regulating Cell Junctions and ROS Generation in Rats","volume":"43","author":"Li","year":"2018","journal-title":"Curr. Eye Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/j.1476-5381.2008.00087.x","article-title":"EPAC proteins transduce diverse cellular actions of cAMP","volume":"158","author":"Borland","year":"2009","journal-title":"Br. J. Pharm."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1182\/blood-2008-02-138438","article-title":"Role of the small GTPase Rap1 for integrin activity regulation in endothelial cells and angiogenesis","volume":"113","author":"Carmona","year":"2009","journal-title":"Blood"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1182\/blood-2007-08-109710","article-title":"Defective angiogenesis, endothelial migration, proliferation, and MAPK signaling in Rap1b-deficient mice","volume":"111","author":"Kraus","year":"2008","journal-title":"Blood"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1097\/MOH.0000000000000332","article-title":"Rap1 in endothelial biology","volume":"24","year":"2017","journal-title":"Curr. Opin. Hematol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"20752","DOI":"10.1074\/jbc.M700487200","article-title":"IQGAP1 binds Rap1 and modulates its activity","volume":"282","author":"Jeong","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.4049\/jimmunol.1102439","article-title":"IQGAP1: A regulator of intracellular spacetime relativity","volume":"188","author":"Malarkannan","year":"2012","journal-title":"J. Immunol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"4347","DOI":"10.1074\/jbc.M208579200","article-title":"Elucidation of the interaction of calmodulin with the IQ motifs of IQGAP1","volume":"278","author":"Li","year":"2003","journal-title":"J. Biol. Chem."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2414\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:17Z","timestamp":1760166137000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2414"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,14]]},"references-count":96,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["cells10092414"],"URL":"https:\/\/doi.org\/10.3390\/cells10092414","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,14]]}}}