Hypoxia-Suppressed Dicer and AGO1 Promote Angiogenesis

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DESCRIPTION (provided by applicant): Project Summary/Abstract: Hypoxia-suppressed Dicer and AGO1 promote angiogenesis Hypoxia-induced angiogenesis is a critical and complex process in normal development and disease conditions such as ischemia. In response to hypoxia, vascular endothelial cells (ECs) selectively upregulate a panel of angiogenic molecules through an intricately coordinated network consisting of transcriptional and post-transcriptional controls to support angiogenesis and new vessel formation. MicroRNAs (miRNAs or miRs) have emerged as essential regulators that modulate gene expression at post-transcriptional level. The regulatory mechanisms of miRNAs and their functional relevance have been intensively investigated in cardiovascular biology and other fields. Most studies to date have focused on transcriptional regulation of miRNAs and functional validation of single miRNA-single target pathways. I recently demonstrated that hypoxia induces a group of hypoxia-responsive miRNAs (HRMs) including Let-7 and miR-103/107, which jointly suppress Dicer and Argonaute 1 (AGO1), two key components of miRNA machinery. The marked decrease of Dicer and AGO1 indicate that hypoxia may cause a global reprogramming of miRNA biogenesis and targeting at post- transcriptional level. Gain- and loss-of-function experiments provide evidence that hypoxia- suppressed Dicer and AGO1 enhance expression of angiogenic factors in ECs, e.g. vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and placental growth factor (PlGF) and hence promote angiogenesis. Mechanistically, hypoxia-suppressed Dicer may alter miRNA biogenesis to promote selective processing of HRMs, which acts in concert with hypoxia- suppressed AGO1 to decrease the miRISC targeting of angiogenic molecules. These observations prompted me to hypothesize that hypoxia-suppressed Dicer and AGO1 alter miRNA biogenesis and miRNA targeting, which enhances the expression of genes promoting angiogenesis. To test this hypothesis, I proposed three specific aims: In Aim 1, I will investigate the molecular basis by which the hypoxia-suppressed Dicer reprograms miRNA biogenesis in ECs to enhance the expression of angiogenic molecules. In Aim 2, I will delineate the mechanism by which hypoxia- suppressed AGO1 regulates miRNA targetome in ECs to promote angiogenesis. In Aim 3, I will examine the functional relevance of hypoxia-suppressed Dicer and AGO1 in pathological angiogenesis, i.e., in the context of myocardial ischemia. Collectively, these studies will reveal a new paradigm of miRNA-regulated gene expression in ECs responding to hypoxic and ischemic stress. Furthermore, the delineated pathways may provide novel insights into future translational studies involving pathological angiogenesis.