MicroRNA-132–mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis
Authors: David J Shields
Lisette M Acevedo
Jeffrey N Lindquist
Eric A Murphy
Miller Huang
Philip E Lapinski
Sara M Weis
Rajesh Mukthavaram
Philip D King
Sudarshan Anand
Lea Scheppke
Bharat K Majeti
David A Cheresh
Journal: Nature Medicine (2010)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: tumors; angiogenic switch; miR-132; p120RasGAP; endothelium
Affiliations: Department of Pathology, University of California, San Diego, California, USA.

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. 

Retracted: No

PubPeer comments:
 The authors seem to have accidentally duplicated one of the images in Figure 5 of the Supplemental Materials. ![file] On the topic of reusing images, I will also note that, as a detail-oriented reader, I find it somewhat frustrating that the  representative images of the angiogenesis feature a lot of reuse. In Figure 1 in the main manuscript, the authors contrast anti-mIR 132-injected mice with controls. There were 5 mice per group, yet, for the treated group, we are treated twice to what is essentially the same image. ![file] Suddenly, we wonder how representative that image is of the group as a whole. Surely the authors could have used images from two *different* mice? Or even images spaced further apart? We see more of this in Figure 5 of the supplemental materials. ![file] ![file] By using images from *different* mice, the authors would better be able to dispell the feeling that we are only shown what the authors will allow us to see. I am not sure whether the authors still have the original images, but perhaps this can serve as food for thought down the road..? ,