MicroRNA Regulation of the Pathological Angiogenic Response
During development, pro- and anti-angiogenic factors orchestrate a complex, dynamic process to allow initial sprouting and invasion, subsequent pruning and remodeling, and finally maturation and survival of blood vessels. However, in pathological conditions such as cancer, diabetic retinopathy, macular degeneration or inflammation the same angiogenic signaling pathways are misregulated and exploited, typically resulting in poorly organized vessels with leaky and tortuous properties. In the last decade, a new class of small non-coding RNA molecules termed microRNAs (miRs) have emerged as key regulators of several cellular processes including angiogenesis.
We recently profiled microRNAs that were regulated upon growth factor activation of human endothelial cells and identified miR-132 as a regulator of pathological neovascularization. We found that miR-132 was highly expressed in activated blood vessels, but was undetectable in normal endothelium. Ectopic expression of miR-132 in endothelial cells increased their proliferation and tube-forming capacity, whereas intraocular injection of an antagomir targeting miR-132, reduced postnatal retinal vascular development in mice. We identified p120RasGAP as a miR-132 target and showed that miR-132 and p120RasGAP are expressed reciprocally during pathological angiogenesis. Our observations in several in vitro and in vivo models suggest 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.
In contrast to miR-132, a highly upregulated miR during angiogenesis, we have identified miR-34 as one of the most downregulated microRNAs in response to growth factors. Conversely, miR-34a is highly upregulated during endothelial stress responses. Our observations suggest that miR-34a functions as an ‘apoptomiR’ mediating endothelial cell death during stress by regulating the Notch pathway. Taken together, our data suggests a broad regulatory network of pro and anti-angiogenic microRNAs that target defined pathways to co-ordinate vascular responses in development and disease.
- © 2011 by American Heart Association, Inc.