Coronary adventitial cells are linked to perivascular cardiac fibrosis via TGFβ1 signaling in the mdx mouse model of Duchenne muscular dystrophy (original) (raw)

2013, Journal of Molecular and Cellular Cardiology

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+, PDGFR +, CD31−, CD45− coronary adventitial cells responsible for perivascular fibrosis. Histopathology of dystrophic hearts revealed Sca1+ cells extend from the adventitia and occupy regions of perivascular fibrosis. The number of Sca1+ adventitial cells increased twofold in fibrotic mdx hearts vs. age matched wild-type hearts. Moreover, relative to Sca1−, PDGFR +, CD31−, CD45− cells and endothelial cells, Sca1+ adventitial cells FACS-sorted from mdx hearts expressed the highest level of Collagen1 1 and 3 1, Connective tissue growth factor, and Tgf r1 transcripts. Surprisingly, mdx endothelial cells expressed the greatest level of the Tgf 1 ligand. Utilizing Collagen1 1-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 PDGFR + but negative for Sca1. Treatment of cultured Collagen1 1-GFP+ adventitial cells with TGF 1 resulted in increased collagen synthesis, whereas pharmacological inhibition of TGF R1 signaling reduced the fibrotic response. Therefore, perivascular cardiac fibrosis by coronary adventitial cells may be mediated by TGF 1 signaling. Our results implicate coronary endothelial cells in mediating cardiac fibrosis via transmural TGF signaling, and suggest that the coronary adventitia is a promising target for developing novel antifibrotic therapies.