MicroRNA-148b Targets the TGF-β Pathway to Regulate Angiogenesis and Endothelial-to-Mesenchymal Transition during Skin Wound Healing

Vladislav Miscianinov, Andrea Martello, Lorraine Rose, Elisa Parish, Ben Cathcart, Tijana Mitić, Gillian A. Gray, Marco Meloni, Ayman Al Haj Zen, Andrea Caporali*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)

Abstract

Transforming growth factor beta (TGF-β) is crucial for regulation of the endothelial cell (EC) homeostasis. Perturbation of TGF-β signaling leads to pathological conditions in the vasculature, causing cardiovascular disease and fibrotic disorders. The TGF-β pathway is critical in endothelial-to-mesenchymal transition (EndMT), but a gap remains in our understanding of the regulation of TGF-β and related signaling in the endothelium. This study applied a gain- and loss-of function approach and an in vivo model of skin wound healing to demonstrate that miR-148b regulates TGF-β signaling and has a key role in EndMT, targeting TGFB2 and SMAD2. Overexpression of miR-148b increased EC migration, proliferation, and angiogenesis, whereas its inhibition promoted EndMT. Cytokine challenge decreased miR-148b levels in ECs while promoting EndMT through the regulation of SMAD2. Finally, in a mouse model of skin wound healing, delivery of miR-148b mimics promoted wound vascularization and accelerated closure. In contrast, inhibition of miR-148b enhanced EndMT in wounds, resulting in impaired wound closure that was reversed by SMAD2 silencing. Together, these results demonstrate for the first time that miR-148b is a key factor controlling EndMT and vascularization. This opens new avenues for therapeutic application of miR-148b in vascular and tissue repair.

Original languageEnglish
Pages (from-to)1996-2007
Number of pages12
JournalMolecular Therapy
Volume26
Issue number8
DOIs
Publication statusPublished - 1 Aug 2018
Externally publishedYes

Keywords

  • TGF-β
  • angiogenesis
  • endothelial-to-mesenchymal transition
  • microRNAs
  • wound healing

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