title: Coronary adventitial cells are linked to perivascular cardiac fibrosis via TGFβ1 signaling in the mdx mouse model of Duchenne muscular dystrophy.
abstract: In Duchenne muscular dystrophy (DMD), progressive accumulation of cardiac fibrosis promotes heart failure. While the cellular origins of fibrosis in DMD hearts remain enigmatic, fibrotic tissue conspicuously forms near the coronary adventitia. Therefore, we sought to characterize the role of coronary adventitial cells in the formation of perivascular fibrosis. Utilizing the mdx model of DMD, we have identified a population of Sca1+, PDGFRα+, CD31-, and CD45- coronary adventitial cells responsible for perivascular fibrosis. Histopathology of dystrophic hearts revealed that Sca1+ cells extend from the adventitia and occupy regions of perivascular fibrosis. The number of Sca1+ adventitial cells increased two-fold in fibrotic mdx hearts vs. age matched wild-type hearts. Moreover, relative to Sca1-, PDGFRα+, CD31-, and CD45- cells and endothelial cells, Sca1+ adventitial cells FACS-sorted from mdx hearts expressed the highest level of Collagen1α1 and 3α1, Connective tissue growth factor, and Tgfβr1 transcripts. Surprisingly, mdx endothelial cells expressed the greatest level of the Tgfβ1 ligand. Utilizing Collagen1α1-GFP reporter mice, we confirmed that the majority of Sca1+ adventitial cells expressed type I collagen, an abundant component of cardiac fibrosis, in both wt (71%±4.1) and mdx (77%±3.5) hearts. In contrast, GFP+ interstitial fibroblasts were PDGFRα+ but negative for Sca1. Treatment of cultured Collagen1α1-GFP+ adventitial cells with TGFβ1 resulted in increased collagen synthesis, whereas pharmacological inhibition of TGFβR1 signaling reduced the fibrotic response. Therefore, perivascular cardiac fibrosis by coronary adventitial cells may be mediated by TGFβ1 signaling. Our results implicate coronary endothelial cells in mediating cardiac fibrosis via transmural TGFβ signaling, and suggest that the coronary adventitia is a promising target for developing novel anti-fibrotic therapies.
authors.affiliation: Department of Pathology, School of Medicine, University of Washington, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ieronimakis
authors.forename: Aislinn L
authors.initials: AL
authors.lastname: Hays
authors.forename: Kajohnkiart
authors.initials: K
authors.lastname: Janebodin
authors.forename: William M
authors.initials: WM
authors.lastname: Mahoney
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
authors.forename: Mark W
authors.initials: MW
authors.lastname: Majesky
authors.forename: Morayma
authors.initials: M
authors.lastname: Reyes
mesh_terms: D063194:Adventitia / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D009202:Cardiomyopathies / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics; D007422:Intestines / Q000166:cytology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000150:complications*; D020286:Pericytes; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D000950:Antigens, Ly; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D053773:Transforming Growth Factor beta1
keywords: Adventitia; Fibrosis; Muscular dystrophy; Perivascular; Sca1; TGFβ1; Type I collagen
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