Long Non-Coding RNAs and Cerebral Angiogenesis in Ischemic Stroke

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Extensive evidence has shown that post-ischemia angiogenesis contributes to the improvement of blood flow and neurological outcomes in stroke. Cerebral ischemia rapidly triggers the induction of a variety of genes and proteins that are involved in angiogenesis. Interventions that enhance these pro-angiogenic factors are a promising therapeutic strategy for long-term functional recovery after ischemic stroke. Long non-coding RNAs (lncRNAs) function as a novel class of noncoding RNAs that modulate gene or protein expression. In addition to their critical role in various biological processes, lncRNAs have also been implicated in a variety of human neurological diseases. We and others have recently uncovered the essential role of lncRNAs in the pathogenesis of ischemic injury in rodent stroke models, suggesting that lncRNAs are potential therapeutic targets. However, the functional significance and molecular mechanisms of lncRNAs in angiogenesis and late stage of neurological outcomes after ischemic stroke are poorly understood. Metastasis associated lung adenocarcinoma transcript 1 (Malat1) is one of the first identified lncRNAs associated with human cancers. Cumulative studies have shown that Malat1 plays pivotal roles in multiple pathological conditions as well. Previously, we were the first to identify that (Malat1) is one of the most highly upregulated stroke-responsive endothelial lncRNAs by using RNA-sequencing technology, and its dysfunction contributes to acute ischemic brain injury. We also demonstrated that Malat1 can significantly suppress cell- autonomous angiogenesis in hindlimb ischemia. Moreover, our preliminary studies showed that Malat1 levels are significantly increased in the cerebral vasculature of the penumbral area 7d after middle cerebral artery occlusion (MCAO) in mice. Of note, genetic deletion of Malat1 leads to reduced cerebral microvessel density and increased brain atrophy in mice 28d after MCAO, whereas EC-selective transgenic overexpression of the Malat1 gene increases post-ischemic cerebral angiogenesis in mice. Furthermore, we found that genetic deletion of Malat1 effectively inhibits VEGF mRNA and protein expression in isolated mouse brain microvessels 7 d after ischemic stroke. These findings have provided the basis for our Central Hypothesis that Malat1 functions as a critical regulator in post-ischemic cerebral angiogenesis, thus affecting long-term neurological outcomes after ischemic stroke. Three aims will be performed in this proposal. Aim 1: Examine the functional role of Malat1 in regulating post-stroke angiogenesis; Aim 2: Identify the molecular targets of Malat1 in regulating post-stroke angiogenesis; Aim 3: Determine whether Malat1-mediated angiogenesis affects long-term stroke outcomes. Elucidating the essential role of Malat1 in post-stroke angiogenesis and the underlying mechanism may eventually lead us to identify novel neurorestorative targets for the treatment of ischemic stroke.