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.
Highlights
It is well known that the transforming growth factor beta (TGF-b) signaling pathway plays a crucial role in the regulation of vascular function in health and disease.[1]
Phosphorylation of ALK5 by TGFBR2 kinase activates its catalytic kinase domain allowing the activation of the receptorregulated Smads (i.e., SMAD2 and SMAD3), which translocate to the nucleus, where they regulate the transcription of specific target genes.[2]
We investigated the role of miR-148b on the functional properties of endothelial cell (EC). miR-148b overexpression significantly increased the proliferation of human umbilical vein EC (HUVECs), as demonstrated by bromodeoxyuridine (BrdU) incorporation (Figure 1E)
Summary
It is well known that the transforming growth factor beta (TGF-b) signaling pathway plays a crucial role in the regulation of vascular function in health and disease.[1]. Loss of vascular endothelial cadherin (VE-cadherin) and platelet-EC adhesion molecule 1 (PECAM-1, CD31) are observed along with elevated expression of a-smooth muscle actin (a-SMA), vimentin (VIM), N-cadherin, and extracellular matrix (ECM) proteins like collagen type I and III.[7] ECs undergoing EndMT exhibit cytoskeletal rearrangement, resulting in a change in cell polarity whereby they acquire a stretched and more fibroblast-like morphology.[7] Recently, EndMT has been reported to play an important role during the embryonic stages of cardiac and pulmonary artery development.[8,9] In addition, EndMT has a pathological role through promoting tumor growth and progression,[10] contributing to cardiac[11] and renal fibrosis[12] as well as vascular remodelling[13] and atherosclerosis.[14]
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