Abstract 11383: MicroRNA-100 is an Anti-Angiogenic Modulator in Endothelial Cells
Background: The adaptive growth of blood vessels is an important protective mechanism in cardiovascular disease. However, the underlying regulatory mechanisms of this process are only partly understood. Recently, small endogenous RNAs (microRNAs) were found to play an important role in embryonic and postnatal vascular development. Here, we used microRNA-transcriptome analysis following induction of hindlimb ischemia in mice to screen for microRNAs involved in adaptive blood vessel growth following arterial occlusion.
Methods and Results: Using microRNA-arrays, we explored the microRNA-expression profile during adaptive neovascularization. We describe specific changes in microRNA-expression patterns and show that the microRNA miR-100 is significantly downregulated after induction of hindlimb ischemia in mice. Our in vitro and in vivo data demonstrate that miR-100 modulates proliferation, tube formation and sprouting activity of endothelial cells and functions as an endogenous repressor of the serine/threonine protein kinase mTOR. Whereas miR-100 inhibition increased mTOR-levels in endothelial cells, overexpression of miR-100 reduced mTOR-expression and consequently attenuated cellular proliferation. Supporting this notion, overexpression of a mTOR-construct lacking the miRNA-binding site rescued the inhibitory effect of miR-100 on cell proliferation. Accordingly, miR-100 inhibition by specific antagomirs in vivo stimulated angiogenesis in subcutaneously implanted matrigel plugs and resulted in functional improvement of perfusion after femoral artery occlusion in mice. In contrast, treatment with the mTOR-inhibitor rapamycin had the opposite effect.
Conclusions: Our data demonstrates that miR-100 has an anti-angiogenic function and represses mTOR-signalling in endothelial cells. Inhibition of miR-100 could be a novel approach for the modulation of blood vessel growth and other mTOR-dependent processes.
- © 2010 by American Heart Association, Inc.