Role of αv integrins on perivascular mesenchymal cells in regulation of skeletal and cardiac muscle fibrosis

Abstract

BackgroundMuscle fibrosis is a major global health-care burden. Although cells expressing platelet-derived growth factor receptor β (PDGFRβ) are important in liver fibrosis, their contribution to skeletal and cardiac muscle fibrogenesis remains unclear. Using PDGFRβ-Cre mice, we aimed to identify a pathway driving both skeletal and cardiac muscle fibrosis, focusing on αv integrins and their activation of transforming growth factor β (TGFβ), a central mediator of fibrosis. MethodsThe contribution of PDGFRβ+ cells to muscle fibrosis was assessed in fluorescent reporter (mTmG) mice under the control of PDGFRβ-Cre. Itgavflox/flox;PDGFRβ-Cre mice were used to investigate whether loss of αv integrins influences fibrosis development after cardiotoxin-induced muscle injury and in an angiotensin II model of cardiac fibrosis. A small-molecule inhibitor of αv integrins (CWHM12) and control enantiomer (CWHM96) were used to determine whether pharmacological blockade of αv integrins could attenuate fibrosis. FindingsPDGFRβ-Cre effectively targeted quiescent PDGFRβ+ cells and activated myofibroblasts in both skeletal and cardiac muscle. αv integrin depletion on PDGFRβ+ cells protected mice from cardiotoxin-induced skeletal muscle fibrosis and angiotensin II-induced cardiac fibrosis. In addition, CWHM12 attenuated fibrosis, even when pre-established, in both skeletal and cardiac muscle. αv integrin blockade also reduced TGFβ activation in primary human skeletal muscle and cardiac PDGFRβ+ cells, further highlighting the potential clinical utility of small-molecule αv integrin inhibition in the treatment and prevention of a broad range of muscle fibroses. InterpretationWe have demonstrated that PDGFRβ-Cre labels profibrotic cells in skeletal muscle and that depletion of αv integrins in these cells using this genetic strategy reduces skeletal muscle fibrosis. Most importantly from a treatment standpoint, we have shown that pharmacological inhibition of αv integrins with a small-molecule inhibitor might have utility in the prevention and treatment of established skeletal muscle fibrosis. FundingWellcome Trust, British Heart Foundation, Royal College of Surgeons of Edinburgh.