1. Molecular Medicine Unit, UCL Institute of Child Health, London WC1N 1EH, UK
2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
3. Massachusetts General Hospital Cardiovascular Research Center, Boston, Massachusetts 02114, USA, and the Department of Cell Biology, Harvard Medical School, and the Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA

Correspondence to: Paul R. Riley¹ Correspondence and requests for materials should be addressed to P.R.R. (Email: P.Riley@ich.ucl.ac.uk).

Abstract

Cardiac failure has a principal underlying aetiology of ischaemic damage arising from vascular insufficiency. Molecules that regulate collateral growth in the ischaemic heart also regulate coronary vasculature formation during embryogenesis. Here we identify thymosin 4 (T4) as essential for all aspects of coronary vessel development in mice, and demonstrate that T4 stimulates significant outgrowth from quiescent adult epicardial explants, restoring pluripotency and triggering differentiation of fibroblasts, smooth muscle cells and endothelial cells. T4 knockdown in the heart is accompanied by significant reduction in the pro-angiogenic cleavage product N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). Although injection of AcSDKP was unable to rescue T4 mutant hearts, it significantly enhanced endothelial cell differentiation from adult epicardially derived precursor cells. This study identifies T4 and AcSDKP as potent stimulators of coronary vasculogenesis and angiogenesis, and reveals T4-induced adult epicardial cells as a viable source of vascular progenitors for continued renewal of regressed vessels at low basal level or sustained neovascularization following cardiac injury.

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