MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells

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Arquivos
art_ICLI_MicroRNA135a3p_regulates_angiogenesis_and_tissue_repair_by_targeting_2019.PDF (2.49 MB)
Citações na Scopus
53
Tipo de produção
article
Data de publicação
2019
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
FEDERATION AMER SOC EXP BIOL
Autores
ICLI, Basak
WU, Winona
OZDEMIR, Denizhan
LI, Hao
HAEMMIG, Stefan
LIU, Xin
GIATSIDIS, Giorgio
CHENG, Henry S.
AVCI, Seyma Nazli
KURT, Merve
Citação
FASEB JOURNAL, v.33, n.4, p.5599-5614, 2019
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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.
Palavras-chave
VEGF, diabetic wounds, human organoid
URI
https://observatorio.fm.usp.br/handle/OPI/31902
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Coleções
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/13
Artigos e Materiais de Revistas Científicas - ODS/03