Thymosin β4 and the vasculature: multiple roles in development, repair and protection against disease

ABSTRACT

Introduction: Formation of the vasculature is a complex process, defects in which can lead to embryonic lethality or disease in later life. Understanding mechanisms of vasculogenesis may facilitate the treatment of developmental defects and may be extrapolated to promote wound healing and tissue repair. Thymosin β4 (Tβ4) is an actin monomer binding protein with recognized roles in vascular development, neovascularization and protection against disease.

Areas covered: Vascular network assembly is complex, regulated by multiple signals and cell types; Tβ4 functions in many of the underlying processes, including vasculogenesis, angiogenesis, arteriogenesis, endothelial-mesenchymal transition and extracellular matrix remodeling. Loss of Tβ4 perturbs vessel growth and stability, whereas exogenous application enhances capillary formation and pericyte recruitment, during development and in injury models.

Expert opinion: Although vascular functions for Tβ4 have been well documented, the underlying molecular mechanisms remain obscure. While Tβ4-induced cytoskeletal remodeling likely mediates the directional migration of endothelial cells, paracrine roles have also been implicated in migration and differentiation of smooth muscle cells. Moreover, nuclear functions of Tβ4 have been described but remain to be explored in the vasculature. Delineati+ng the molecular pathways impacted by Tβ4 to promote vascular growth and remodeling may reveal novel targets for prevention and treatment of vascular disease.

KEYWORDS:

• Angiogenesis
• arteriogenesis
• endocardium
• endothelial cells
• endothelial-mesenchymal transition
• epicardium
• neovascularization
• smooth muscle differentiation
• thymosin β4
• vasculogenesis

Article highlights

Tβ4, an actin monomer binding peptide, has been shown to play multiple key roles in the vasculature, including vasculogenesis, angiogenesis and smooth muscle cell differentiation.

Tβ4 plays an essential role in development of the yolk sac, coronary and systemic vasculature.

Exogenously applied Tβ4 promotes neovascularization in ischemic tissues and accounts, at least in part, for the pro-angiogenic effects of stem cell therapy.

Expression of Tβ4 in the aorta and up-regulation in disease settings suggests a possible role in homeostasis and vascular protection and warrants further investigation.

Further insight into the role of Tβ4, such that it may be targeted therapeutically, requires a comprehensive understanding of its molecular mechanism of action.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have nothing to disclose.

Additional information

Funding

This research has been funded by the British Heart Foundation. This paper has been published as part of a supplement issue covering the proceedings of the Fifth International Symposium on Thymosins in Health and Disease and is funded by SciClone Pharmaceuticals.