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

Icli B., Wu W., Ozdemir D., Li H., Haemmig S., Liu X., ...More

FASEB JOURNAL, vol.33, no.4, pp.5599-5614, 2019 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 33 Issue: 4
  • Publication Date: 2019
  • Doi Number: 10.1096/fj.201802063rr
  • Journal Name: FASEB JOURNAL
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.5599-5614
  • Hacettepe University Affiliated: No


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.