An Essential Role for Thymosin β4 in Regulating Vascular Smooth Muscle Cell Development and Vessel Wall Stability
Rationale: Compromised development of blood vessel walls leads to vascular instability which may predispose to aneurysm with risk of rupture and lethal haemorrhage. There is currently a lack of insight into developmental insults which may define the molecular and cellular characteristics of initiating and perpetrating factors in adult aneurismal disease.
Objective: To investigate a role for the actin binding protein, Thymosin β4 (Tβ4), previously shown to be pro-angiogenic, in mural cell development and vascular wall stability.
<em>Methods and Results:</em> Phenotypic analyses of both global and endothelial-specific loss of function Tβ4 mouse models revealed a proportion of Tβ4 -null embryos with vascular haemorrhage coincident with a reduction in smooth muscle cell coverage of their developing vessels. Mechanistic studies revealed that extracellular Tβ4 can stimulate differentiation of mesodermal progenitor cells to a mature mural cell phenotype through activation of the TGF β pathway and that reduced TGFβ -signalling correlates with the severity of haemorrhagic phenotype in Tβ4 -null vasculature.
Conclusions: Tβ4 is a novel endothelial secreted trophic factor which functions synergistically with TGFβ to regulate mural cell development and vascular wall stability. These findings have important implications for understanding congenital anomalies that may be causative for adult-onset vascular instability.
- Mouse mutants
- Smooth muscle differentiation
- Vascular biology
- Vascular smooth muscle
- mural cell
- Received October 27, 2011.
- Accepted June 18, 2012.
- Copyright © 2012, American Heart Association