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

Research output: Contribution to journalArticlepeer-review

Abstract

Transforming growth factor beta (TGF-b) is crucial for regulation of the endothelial cell (EC) homeostasis. Perturbation of TGF-b signaling leads to pathological conditions in the vasculature, causing cardiovascular disease and fibrotic disorders. The TGF-b pathway is critical in endothelial-tomesenchymal transition (EndMT), but a gap remains in our understanding of the regulation of TGF-b and related signaling in the endothelium. This study applied a gainand loss-of function approach and an in vivo model of skin wound healing to demonstrate that miR-148b regulates TGF-b 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
JournalMolecular Therapy
Volume26
Issue number8
Early online date8 May 2018
DOIs
Publication statusPublished - 1 Aug 2018

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