title: FGF2 inhibits endothelial-mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling.
abstract: Endothelial-to-mesenchymal transition (EndMT) is characterized by the loss of endothelial cell markers and functions, and coincides with de novo expression of mesenchymal markers. EndMT is induced by TGFβ1 and changes endothelial microRNA expression. We found that miR-20a is decreased during EndMT, and that ectopic expression of miR-20a inhibits EndMT induction. TGFβ1 induces cellular hypertrophy in human umbilical vein endothelial cells and abrogates VE-cadherin expression, reduces endothelial sprouting capacity and induces the expression of the mesenchymal marker SM22α (also known as TAGLN). We identified ALK5 (also known as TGFBR1), TGFBR2 and SARA (also known as ZFYVE9) as direct miR-20a targets. Expression of miR-20a mimics abrogate the endothelial responsiveness to TGFβ1, by decreasing ALK5, TGFBR2 and SARA, and inhibit EndMT, as indicated by the maintenance of VE-cadherin expression, the ability of the cells to sprout and the absence of SM22α expression. FGF2 increases miR-20a expression and inhibits EndMT in TGFβ1-stimulated endothelial cells. In summary, FGF2 controls endothelial TGFβ1 signaling by regulating ALK5, TGFBR2 and SARA expression through miR-20a. Loss of FGF2 signaling combined with a TGFβ1 challenge reduces miR-20a levels and increases endothelial responsiveness to TGFβ1 through elevated receptor complex levels and activation of Smad2 and Smad3, which culminates in EndMT.
authors.affiliation: From the Cardiovascular Regenerative Medicine Research Group, Dept. Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen 9713 GZ, The Netherlands.
authors.forename: Ana C P
authors.initials: AC
authors.lastname: Correia
authors.affiliation: From the Cardiovascular Regenerative Medicine Research Group, Dept. Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen 9713 GZ, The Netherlands.
authors.forename: Jan-Renier A J
authors.initials: JR
authors.lastname: Moonen
authors.affiliation: From the Cardiovascular Regenerative Medicine Research Group, Dept. Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen 9713 GZ, The Netherlands.
authors.forename: Marja G L
authors.initials: MG
authors.lastname: Brinker
authors.affiliation: From the Cardiovascular Regenerative Medicine Research Group, Dept. Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), Groningen 9713 GZ, The Netherlands g.krenning@umcg.nl.
authors.forename: Guido
authors.initials: G
authors.lastname: Krenning
mesh_terms: D015703:Antigens, CD; D015415:Biomarkers / Q000378:metabolism; D015820:Cadherins; D054338:Cell Transdifferentiation / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D015820:Cadherins; D016222:Fibroblast Growth Factor 2; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D012697:Serine Endopeptidases; D053773:Transforming Growth Factor beta1; D000099152:Cadherin 5; C534451:MIRN20a microRNA, human; C508960:TGFB1 protein, human; C000625841:TGFBR1 protein, human; C116420:ZFYVE16 protein, human
keywords: EndMT; Endothelial cell; Endothelial dysfunction; Endothelial–mesenchymal transition; FGF; Fibroblast growth factor; MicroRNA; TGFβ; Transforming growth factor beta; miRNA