Coronary Adventitial Cells Are Linked to Perivascular Cardiac Fibrosis Via TGFβ1 Signaling in the Mdx Mouse Model of Duchenne Muscular Dystrophy

Overview

Journal J Mol Cell Cardiol

Specialty Cardiology & Vascular Diseases

Date 2013 Aug 6

PMID 23911435

Citations 34

Authors

Nicholas Ieronimakis

Aislinn L Hays

Kajohnkiart Janebodin

William M Mahoney Jr

Jeremy S Duffield

Mark W Majesky

Morayma Reyes

Affiliations

Soon will be listed here.

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.

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References

Goel S, Guo L, Shi X, Kundi R, Sovinski G, Seedial S . Preferential secretion of collagen type 3 versus type 1 from adventitial fibroblasts stimulated by TGF-β/Smad3-treated medial smooth muscle cells. Cell Signal. 2013; 25(4):955-60. PMC: 3595331. DOI: 10.1016/j.cellsig.2012.12.021. View

Wheeler M, McNally E . The interaction of coronary tone and cardiac fibrosis. Curr Atheroscler Rep. 2005; 7(3):219-26. DOI: 10.1007/s11883-005-0010-8. View

Matsuura K, Nagai T, Nishigaki N, Oyama T, Nishi J, Wada H . Adult cardiac Sca-1-positive cells differentiate into beating cardiomyocytes. J Biol Chem. 2004; 279(12):11384-91. DOI: 10.1074/jbc.M310822200. View

Wrana J, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M . TGF beta signals through a heteromeric protein kinase receptor complex. Cell. 1992; 71(6):1003-14. DOI: 10.1016/0092-8674(92)90395-s. View

Liu X, Wu H, Byrne M, Krane S, Jaenisch R . Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. Proc Natl Acad Sci U S A. 1997; 94(5):1852-6. PMC: 20006. DOI: 10.1073/pnas.94.5.1852. View

Onofre-Oliveira P, Santos A, Martins P, Ayub-Guerrieri D, Vainzof M . Differential expression of genes involved in the degeneration and regeneration pathways in mouse models for muscular dystrophies. Neuromolecular Med. 2012; 14(1):74-83. DOI: 10.1007/s12017-012-8172-3. View

Stuckey D, Carr C, Camelliti P, Tyler D, Davies K, Clarke K . In vivo MRI characterization of progressive cardiac dysfunction in the mdx mouse model of muscular dystrophy. PLoS One. 2012; 7(1):e28569. PMC: 3250389. DOI: 10.1371/journal.pone.0028569. View

Holmes C, Stanford W . Concise review: stem cell antigen-1: expression, function, and enigma. Stem Cells. 2007; 25(6):1339-47. DOI: 10.1634/stemcells.2006-0644. View

Stuelsatz P, Keire P, Almuly R, Yablonka-Reuveni Z . A contemporary atlas of the mouse diaphragm: myogenicity, vascularity, and the Pax3 connection. J Histochem Cytochem. 2012; 60(9):638-57. PMC: 3524553. DOI: 10.1369/0022155412452417. View

10.

Bishop J, Greenbaum R, Gibson D, Yacoub M, Laurent G . Enhanced deposition of predominantly type I collagen in myocardial disease. J Mol Cell Cardiol. 1990; 22(10):1157-65. DOI: 10.1016/0022-2828(90)90079-h. View

11.

Bostick B, Shin J, Yue Y, Wasala N, Lai Y, Duan D . AAV micro-dystrophin gene therapy alleviates stress-induced cardiac death but not myocardial fibrosis in >21-m-old mdx mice, an end-stage model of Duchenne muscular dystrophy cardiomyopathy. J Mol Cell Cardiol. 2012; 53(2):217-22. PMC: 3389274. DOI: 10.1016/j.yjmcc.2012.05.002. View

12.

Hudon-David F, Bouzeghrane F, Couture P, Thibault G . Thy-1 expression by cardiac fibroblasts: lack of association with myofibroblast contractile markers. J Mol Cell Cardiol. 2007; 42(5):991-1000. DOI: 10.1016/j.yjmcc.2007.02.009. View

13.

Olson L, Soriano P . Increased PDGFRalpha activation disrupts connective tissue development and drives systemic fibrosis. Dev Cell. 2009; 16(2):303-13. PMC: 2664622. DOI: 10.1016/j.devcel.2008.12.003. View

14.

Nisancioglu M, Mahoney Jr W, Kimmel D, Schwartz S, Betsholtz C, Genove G . Generation and characterization of rgs5 mutant mice. Mol Cell Biol. 2008; 28(7):2324-31. PMC: 2268431. DOI: 10.1128/MCB.01252-07. View

15.

Bujak M, Frangogiannis N . The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2006; 74(2):184-95. PMC: 1924687. DOI: 10.1016/j.cardiores.2006.10.002. View

16.

Grygielko E, Martin W, Tweed C, Thornton P, Harling J, Brooks D . Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-beta type I receptor kinase in puromycin-induced nephritis. J Pharmacol Exp Ther. 2005; 313(3):943-51. DOI: 10.1124/jpet.104.082099. View

17.

WEISENFELD S, MESSINGER W . Cardiac involvement in progressive muscular dystrophy. Am Heart J. 1952; 43(2):170-87. DOI: 10.1016/0002-8703(52)90209-3. View

18.

Zhou L, Lu H . Targeting fibrosis in Duchenne muscular dystrophy. J Neuropathol Exp Neurol. 2010; 69(8):771-6. PMC: 2916968. DOI: 10.1097/NEN.0b013e3181e9a34b. View

19.

Zhang W, Ten Hove M, Schneider J, Stuckey D, Sebag-Montefiore L, Bia B . Abnormal cardiac morphology, function and energy metabolism in the dystrophic mdx mouse: an MRI and MRS study. J Mol Cell Cardiol. 2008; 45(6):754-60. DOI: 10.1016/j.yjmcc.2008.09.125. View

20.

Uezumi A, Ito T, Morikawa D, Shimizu N, Yoneda T, Segawa M . Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. J Cell Sci. 2011; 124(Pt 21):3654-64. DOI: 10.1242/jcs.086629. View