TY - JOUR
T1 - Coronary adventitial cells are linked to perivascular cardiac fibrosis via TGFβ1 signaling in the mdx mouse model of Duchenne muscular dystrophy
AU - Ieronimakis, Nicholas
AU - Hays, Aislinn L.
AU - Janebodin, Kajohnkiart
AU - Mahoney, William M.
AU - Duffield, Jeremy S.
AU - Majesky, Mark W.
AU - Reyes, Morayma
N1 - Funding Information:
This work was supported by the American Heart Association award 11BGIA7140028 to M.R., the Seattle Children's Research Institute and NIH grant RO1 HL-093594 to M.W.M., NIH grants HL087513 and HL094374 to W.M.M., the UW Nathan Shock Center of Excellence in the Basic Biology of Aging Genetic Approaches to Aging Training grant T32 AG000057 and Pancretan Association of America Venizelion Scholarship to N.I., and the Anandamahidol Foundation Scholarship of Thailand to K.J.
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
KW - Adventitia
KW - Fibrosis
KW - Muscular dystrophy
KW - Perivascular
KW - Sca1
KW - TGFβ1
KW - Type I collagen
UR - http://www.scopus.com/inward/record.url?scp=84884792732&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884792732&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2013.07.014
DO - 10.1016/j.yjmcc.2013.07.014
M3 - Article
C2 - 23911435
AN - SCOPUS:84884792732
SN - 0022-2828
VL - 63
SP - 122
EP - 134
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -