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Published January 1, 2019 | Version v1
Journal article Open

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

Creators

  • 1. Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Dept Med, 77 Ave Louis Pasteur,NRB-742F, Boston, MA 02115 USA
  • 2. Harvard Med Sch, Brigham & Womens Hosp, Dept Surg, Div Plast Surg, Boston, MA 02115 USA
  • 3. Fundacao Univ Cardiol ICFUC, Inst Cardiol Rio Grande Sul, Porto Alegre, RS, Brazil
  • 4. Univ Sao Paulo, Med Sch, Heart Inst, Sao Paulo, Brazil
  • 5. LHL Hosp Gardermoen, Dept Cardiac Surg, Jessheim, Norway

Description

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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