Ischaemic damage that results from vascular insufficiency is a frequent cause of cardiac failure. Riley and colleagues now identify thymosin 4 (T4), a protein required for actin reorganization, as being essential for all key aspects of coronary vessel development in mice, and demonstrate that T4 stimulates the mobilization of vascular progenitors from adult epicardium.

To investigate the role of T4 in heart development, Riley and colleagues generated mouse embryos with a heart-specific T4 deficiency, designated T4sh^Nk. T4sh^Nk embryos displayed epicardial defects by embryonic day 12.5 (E12.5). By E14.5, these were accompanied by defects in the ventricular myocardium and by E16.5, severely affected embryos were dying.

...T4 and AcSDKP function as potent stimulators of coronary vasculogenesis and angiogenesis, offering protection following cardiac injury.

A lack of immunostaining for the endothelial-specific receptor TIE2 in the myocardium of T4sh^Nk hearts signified the absence of microvessels. By contrast, TIE2 was strongly expressed in aberrant epicardial nodules, which indicates that these nodules represent a population of epicardium-derived cells (EPDCs) that have attempted, but failed, to migrate through the myocardium to form coronary vessels. Moreover, in T4sh^Nk hearts, smooth-muscle cells (which are also derived from EPDCs) failed to migrate into the myocardium to provide support to the coronary vessels. So, T4 knockdown in the heart leads to defects in epicardial cell migration and coronary vessel development.

These defects were non-cell autonomous, which indicates a loss of functional secreted T4 and impaired paracrine signalling to the epicardium. Riley and colleagues therefore investigated the effect of soluble T4 on epicardial explants in vitro. Explants from wild-type embryonic hearts treated with T4 showed significantly increased outgrowths of smooth-muscle cells and TIE2-expressing endothelial cells. So, T4 promotes vascular progenitor proliferation from embryonic epicardium — but can this be translated to a role for T4 in angiogenic therapy for coronary artery disease?

Treatment of adult epicardial explants with T4 stimulated extensive outgrowth of cells that differentiated into endothelial, smooth-muscle and fibroblastic cells. Remarkably, T4-treated adult EPDCs displayed a state of pluripotency equivalent to their embryonic precursors. The authors suggest that these cells could provide a source of endothelial and smooth-muscle vascular precursors for vascular regeneration in the ischaemic heart.

But what are the mechanisms that underlie the vasculogenic function of T4? The role of T4 in actin reorganization could help promote EPDC migration. In addition, T4 is subject to proteinase activity, which results in the pro-angiogenic tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). The level of AcSDKP was lower in T4-mutant hearts. And although injection of AcSDKP was unable to rescue the T4-mutant phenotype, it significantly enhanced endothelial cell differentiation from adult epicardially derived precursor cells. The authors conclude that, together, T4 and AcSDKP function as potent stimulators of coronary vasculogenesis and angiogenesis, offering protection following cardiac injury.

Author: Rebecca Robey - Copyright © 2007 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission