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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 beta4 (Tbeta4) as essential for all aspects of coronary vessel development in mice, and demonstrate that Tbeta4 stimulates significant outgrowth from quiescent adult epicardial explants, restoring pluripotency and triggering differentiation of fibroblasts, smooth muscle cells and endothelial cells. Tbeta4 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 Tbeta4 mutant hearts, it significantly enhanced endothelial cell differentiation from adult epicardially derived precursor cells. This study identifies Tbeta4 and AcSDKP as potent stimulators of coronary vasculogenesis and angiogenesis, and reveals Tbeta4-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.

Original publication

DOI

10.1038/nature05383

Type

Journal article

Journal

Nature

Publication Date

11/01/2007

Volume

445

Pages

177 - 182

Keywords

Animals, Cell Differentiation, Cell Lineage, Cell Movement, Coronary Vessels, Endothelium, Vascular, Female, Mice, Myoblasts, Cardiac, Myocytes, Smooth Muscle, Neovascularization, Physiologic, Organ Specificity, Pericardium, Pregnancy, Stem Cells, Thymosin