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Title: MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells
Authors: ICLI, BasakWU, WinonaOZDEMIR, DenizhanLI, HaoHAEMMIG, StefanLIU, XinGIATSIDIS, GiorgioCHENG, Henry S.AVCI, Seyma NazliKURT, MerveLEE, NathanGUIMARAES, Raphael BoescheMANICA, AndreMARCHINI, Julio F.RYNNING, Stein ErikRISNES, IvarHOLLAN, IvanaCROCE, KevinORGILL, Dennis P.FEINBERG, Mark W.
Citation: FASEB JOURNAL, v.33, n.4, p.5599-5614, 2019
Abstract: Angiogenesis is a critical process in repair of tissue injury that is regulated by a delicate balance between pro- and antiangiogenic factors. In disease states associated with impaired angiogenesis, we identified that miR-135a-3p is rapidly induced and serves as an antiangiogenic microRNA (miRNA) by targeting endothelial cell (EC) p38 signaling in vitro and in vivo. MiR-135a-3p overexpression significantly inhibited EC proliferation, migration, and network tube formation in matrigel, whereas miR-135-3p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3'-UTR reporter and miRNA ribonucleoprotein complex -immunoprecipitation assays, and small interfering RNA dependency studies revealed that miR-135a-3p inhibits the p38 signaling pathway in ECs by targeting huntingtin-interacting protein 1 (HIP1). Local delivery of miR-135a-3p inhibitors to wounds of diabetic db/db mice markedly increased angiogenesis, granulation tissue thickness, and wound closure rates, whereas local delivery of miR-135a-3p mimics impaired these effects. Finally, through gain- and loss-of-function studies in human skin organoids as a model of tissue injury, we demonstrated that miR-135a-3p potently modulated p38 signaling and angiogenesis in response to VEGF stimulation by targeting HIP1. These findings establish miR-135a-3p as a pivotal regulator of pathophysiological angiogenesis and tissue repair by targeting a VEGF-HIP1-p38K signaling axis, providing new targets for angiogenic therapy to promote tissue repair.
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Artigos e Materiais de Revistas Científicas - HC/ICHC
Instituto Central - HC/ICHC

Artigos e Materiais de Revistas Científicas - LIM/13
LIM/13 - Laboratório de Genética e Cardiologia Molecular

Artigos e Materiais de Revistas Científicas - ODS/03
ODS/03 - Saúde e bem-estar

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