title: ARHGAP18: an endogenous inhibitor of angiogenesis, limiting tip formation and stabilizing junctions.
abstract: The formation of the vascular network requires a tightly controlled balance of pro-angiogenic and stabilizing signals. Perturbation of this balance can result in dysregulated blood vessel morphogenesis and drive pathologies including cancer. Here, we have identified a novel gene, ARHGAP18, as an endogenous negative regulator of angiogenesis, limiting pro-angiogenic signaling and promoting vascular stability. Loss of ARHGAP18 promotes EC hypersprouting during zebrafish and murine retinal vessel development and enhances tumor vascularization and growth. Endogenous ARHGAP18 acts specifically on RhoC and relocalizes to the angiogenic and destabilized EC junctions in a ROCK dependent manner, where it is important in reaffirming stable EC junctions and suppressing tip cell behavior, at least partially through regulation of tip cell genes, Dll4, Flk-1 and Flt-4. These findings highlight ARHGAP18 as a specific RhoGAP to fine tune vascular morphogenesis, limiting tip cell formation and promoting junctional integrity to stabilize the angiogenic architecture.
authors.affiliation: a Centre for the Endothelium; Vascular Biology Program; Centenary Institute ; Newtown , NSW , Australia.
authors.forename: Garry H K
authors.initials: GH
authors.lastname: Chang
authors.forename: Angelina J
authors.initials: AJ
authors.lastname: Lay
authors.forename: Ka Ka
authors.initials: KK
authors.lastname: Ting
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Paul R
authors.initials: PR
authors.lastname: Coleman
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Powter
authors.forename: Ann
authors.initials: A
authors.lastname: Formaz-Preston
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Jolly
authors.forename: Neil I
authors.initials: NI
authors.lastname: Bower
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Hogan
authors.forename: Silke
authors.initials: S
authors.lastname: Rinkwitz
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Becker
authors.forename: Mathew A
authors.initials: MA
authors.lastname: Vadas
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Gamble
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D012160:Retina / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism; D029961:Zebrafish Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C542464:ARHGAP18 protein, human; C000599629:ARHGAP18 protein, mouse; C000599630:ARHGAP18 protein, zebrafish; D020690:GTPase-Activating Proteins; D029961:Zebrafish Proteins; D020741:rho GTP-Binding Proteins
keywords: AJ, Adherens junctions; ARHGAP18; DLL4, Delta-like ligand 4; EC, Endothelial cell; GAP, GTPase activating protein; GDI, Guanine nucleotide dissociation inhibitor; GEF, Guanine nucleotide exchange factor; HUVEC, Human umbilical vein endothelial cell; ISV, Intersegmental vessel; MO, Morpholino; SC, Stalk cell; SENEX; Sp, Splice; TC, Tip cell; Tr, Translational; WT, Wildtype; angiogenesis; cell junctions; hpf, Hours post fertilization; sprouting