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In disease states associated with impaired angiogenesis, we identified that miR\u2010135a\u20103p is rapidly induced and serves as an antiangiogenic microRNA (miRNA) by targeting endothelial cell (EC) p38 signaling\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . MiR\u2010135a\u20103p overexpression significantly inhibited EC proliferation, migration, and network tube formation in matrigel, whereas miR\u2010135\u20103p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3\u2032\u2010UTR reporter and miRNA ribonucleoprotein complex \u2010immunoprecipitation assays, and small interfering RNA dependency studies revealed that miR\u2010135a\u20103p inhibits the p38 signaling pathway in ECs by targeting huntingtin\u2010interacting protein 1 (HIP1). Local delivery of miR\u2010135a\u20103p inhibitors to wounds of diabetic db\/db mice markedly increased angiogenesis, granulation tissue thickness, and wound closure rates, whereas local delivery of miR\u2010135a\u20103p mimics impaired these effects. Finally, through gain\u2010 and loss\u2010of\u2010function studies in human skin organoids as a model of tissue injury, we demonstrated that miR\u2010135a\u20103p potently modulated p38 signaling and angiogenesis in response to VEGF stimulation by targeting HIP1. These findings establish miR\u2010135a\u20103p as a pivotal regulator of pathophysiological angiogenesis and tissue repair by targeting a VEGF\u2010HIP1\u2010p38K signaling axis, providing new targets for angiogenic therapy to promote tissue repair.\u2014Icli, B., Wu, W., Ozdemir, D., Li, H., Haemmig, S., Liu, X., Giatsidis, G., Cheng, H. S., Avci, S. N., Kurt, M., Lee, N., Guimaraes, R. B., Manica, A., Marchini, J. F., Rynning, S. 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