Ischemic cardiovascular disease due to atherosclerotic occlusion of the arteries to the heart, legs, or brain is associated with considerable morbidity, mortality, and health care expenditure in the United States. The induction and orchestration of new blood vessels is critical for tissue repair in response to injur such as myocardial infarction or peripheral artery disease (PAD). In response to pro-angiogenic stimuli, vascular endothelial cells (ECs) are activated to migrate and proliferate to form primary capillaries. However, despite the importance of ECs in neoangiogenesis, our understanding of the mechanisms regulating this process remains poorly understood. MicroRNAs (miRNAs) are small, single-stranded, non-coding RNAs capable of repressing gene expression by base pairing to the 3'untranslated regions (3'-UTRs) of mRNA targets and are involved in a variety of pathophysiological processes in cardiovascular biology, though their function in vascular EC growth and angiogenesis remains poorly defined. We undertook a microarray profiling approach in endothelial cells and identified that pro-angiogenic stimuli, such as VEGF, decreased miR-26a expression, whereas anti-angiogenic stimuli, such as TSP-1, increased miR-26a expression-observations that are recapitulated in both mice and human ischemic paradigms in vivo. Gain and loss-of-function studies reveal that miR-26a overexpression markedly induced cell cycle arrest, inhibited migration, reduced the release of the pro-angiogenic factor VEGF, and impaired network tube formation in matrigel, whereas blockade of miR-26a had the opposite effects. Mechanistically, we find that miR-26a suppressed EC growth by binding uniquely to the 3'UTR of Smad1 and reduced its expression, an effect that decreased Id1 expression and increased cell cycle arrest genes p21 and p27 in ECs. Finally, systemic intravenous administration of miR-26a inhibitors increased blood vessel formation and reduced infarct size compared to mice that received scrambled control antagomiR injections. These observations provide the foundation for the central hypothesis that miR-26a may serve as a critical regulator of EC growth and angiogenic responses. To better understand the precise role of miR-26a in BMP/Smad1 signaling and angiogenesis, three aims are proposed.
In Aim1, we will delineate the upstream mechanisms governing miR-26a expression in ECs.
In Aim2, we will determine the molecular basis for miR-26a's ability to regulate BMP/Smad1 signaling and EC functions critical to angiogenesis.
In Aim3, we will explore the effect of altered miR-26a expression on acute and chronic experimental ischemic injury. The results of these studies will provide insights regarding miR-26a function in EC biology, pathological and physiological angiogenesis, and cardiovascular ischemic states and may provide new targets to promote angiogenesis for ischemic cardiovascular disease.
The endothelial cell is a critical participant of the body's response to impaired blood flow that contributes to disease states such as ischemic diseases of the heart or leg. We have identified a novel microRNA, termed miR-26a, that is dynamically regulated in response to pro- or anti-angiogenic stimuli in endothelial cells and our studies indicate that miR-26a may act to dampen angiogenic responses within the cardiovascular system. The proposed studies will provide a detailed understanding underlying the function of this factor with the goal of developing novel therapies for the treatment of ischemic cardiovascular diseases.
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