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 delivery1 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.

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

“…[83][84][85][86][87] Another peptide ligand, the asparagine-glycine-arginine (NGR) motif peptide, is identified as a ligand for CD13 or aminopeptidase N overexpressed on tumor endothelial cells and tumor cells. 88) NGR motif peptides have been successfully used to deliver drugs as well as liposomes to tumor vasculature.…”

Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch

“…Recently, a large body of literature identified and confirmed a number of miRs that regulate angiogenesis (1)(2)(3)(4)(5)(6)(7)(8).…”

MicroRNAs; easy and potent targets in optimizing therapeutic methods in reparative angiogenesis

“…Moreover, anti‐angiogenic agents that target the VEGFR and bFGF pathways have shown considerable clinical benefits in patients with solid tumours or retinal diseases associated with pathological neovascularization 71, 95.…”

“…In this context, antagonism of endogenous miRNA regulators such as miR‐15s, miR‐23s and miR‐222s that are induced under pathological conditions and also target ‘gatekeepers’ of endothelial activation may represent a powerful strategy to inhibit or activate angiogenesis in a wide range of pathological conditions 29, 45, 71.…”

“…Data also indicate that specific miRNAs such as miR‐130, ‐132, ‐133 are potentially interesting therapeutic targets that can be used to inhibit the initiation of the ischaemic‐induced pathological processes effects by acting on ECs and through VEGF and bFGF pathways 71, 86, 87, 99.…”