Journal Article

MicroRNA-132–mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis

Cheresh, David A, Lindquist, Jeffrey N, Shields, David J, Anand, Sudarshan, King, Philip D, Huang, Miller, Murphy, Eric A, Weis, Sara M, Mukthavaram, Rajesh, Scheppke, Lea, Lapinski, Philip E, Acevedo, Lisette M, Majeti, Bharat K

2010

Overview

Sudarshan Anand et al . show that endothelial cell expression of the microRNA miR-132 targets a negative regulator of Ras pathway signaling and thereby releases a brake to new blood vessel formation. miR-132 expression is upregulated in the endothelium of human hemangioma and tumor samples, and an antagonist of miR-132, delivered specifically to tumor endothelium using an integrin-targeted nanoparticle, was able to inhibit tumor angiogenesis and growth in mice. 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 1 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/337/384/331 / 631/61/51/391/2310 / 631/67/2328 / Animals / Antibodies, Monoclonal - pharmacology / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carcinogenesis / Cell Proliferation / Cells, Cultured / Development and progression / Drug Evaluation, Preclinical / Endothelial Cells - metabolism / Endothelial Cells - physiology / Endothelium / Endothelium, Vascular - metabolism / Endothelium, Vascular - pathology / Genetic aspects / Health aspects / Humans / Infectious Diseases / Injection / letter / Metabolic Diseases / Mice / Mice, Inbred C57BL / MicroRNA / MicroRNAs - antagonists & inhibitors / MicroRNAs - genetics / MicroRNAs - metabolism / MicroRNAs - physiology / Molecular Medicine / Natural history / Neovascularization / Neovascularization, Pathologic - genetics / Neovascularization, Pathologic - metabolism / Neurosciences / p120 GTPase Activating Protein - genetics / p120 GTPase Activating Protein - metabolism / Pathology, Molecular / Retinal Artery - drug effects / Retinal Artery - metabolism / Retinal Artery - pathology / Ribonucleic acid / RNA / RNA Interference - physiology / RNA, Small Interfering - pharmacology / Rodents / Stem cells / Tumors / Up-Regulation - genetics / Up-Regulation - physiology / Veins & arteries