title: MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis.
abstract: Although it is well established that tumors initiate an angiogenic switch, the molecular basis of this process remains incompletely understood. Here we show that the miRNA miR-132 acts as an angiogenic switch by targeting p120RasGAP in the endothelium and thereby inducing neovascularization. We identified miR-132 as a highly upregulated miRNA in a human embryonic stem cell model of vasculogenesis and found that miR-132 was highly expressed in the endothelium of human tumors and hemangiomas but was undetectable in normal endothelium. Ectopic expression of miR-132 in endothelial cells in vitro increased their proliferation and tube-forming capacity, whereas intraocular injection of an antagomir targeting miR-132, anti-miR-132, reduced postnatal retinal vascular development in mice. Among the top-ranking predicted targets of miR-132 was p120RasGAP, which we found to be expressed in normal but not tumor endothelium. Endothelial expression of miR-132 suppressed p120RasGAP expression and increased Ras activity, whereas a miRNA-resistant version of p120RasGAP reversed the vascular response induced by miR-132. Notably, administration of anti-miR-132 inhibited angiogenesis in wild-type mice but not in mice with an inducible deletion of Rasa1 (encoding p120RasGAP). Finally, vessel-targeted nanoparticle delivery of anti-miR-132 restored p120RasGAP expression in the tumor endothelium, suppressed angiogenesis and decreased tumor burden in an orthotopic xenograft mouse model of human breast carcinoma. We conclude that miR-132 acts as an angiogenic switch by suppressing endothelial p120RasGAP expression, leading to Ras activation and the induction of neovascularization, whereas the application of anti-miR-132 inhibits neovascularization by maintaining vessels in the resting state.
authors.affiliation: Department of Pathology, University of California, San Diego, California, USA.
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Anand
authors.forename: Bharat K
authors.initials: BK
authors.lastname: Majeti
authors.forename: Lisette M
authors.initials: LM
authors.lastname: Acevedo
authors.forename: Eric A
authors.initials: EA
authors.lastname: Murphy
authors.forename: Rajesh
authors.initials: R
authors.lastname: Mukthavaram
authors.forename: Lea
authors.initials: L
authors.lastname: Scheppke
authors.forename: Miller
authors.initials: M
authors.lastname: Huang
authors.forename: David J
authors.initials: DJ
authors.lastname: Shields
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Lindquist
authors.forename: Philip E
authors.initials: PE
authors.lastname: Lapinski
authors.forename: Philip D
authors.initials: PD
authors.lastname: King
authors.forename: Sara M
authors.initials: SM
authors.lastname: Weis
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012161:Retinal Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D020729:p120 GTPase Activating Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C547077:MIRN132 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D020729:p120 GTPase Activating Protein