Compromised development of blood vessel walls leads to vascular instability and may predispose to aneurysm with risk of rupture and lethal haemorrhage. Having previously demonstrated a requirement for the actin binding peptide Thymosin β4 (Tβ4) in appropriate migration and differentiation of smooth muscle cells in the coronary and yolk sac vasculature, we investigated its role in systemic vascular development and wall stability.Methods and Results
Phenotypic analyses of both global and endothelial-specific loss of function Tβ4 embryos revealed a partially penetrant haemorrhagic phenotype coincident with a reduction in mural cell coverage of developing vessels. MRI and histological analyses demonstrated that surviving adult mutant mice display increased vascular compliance and aortic dilation arising from a dysfunctional medial layer. Mechanistic studies revealed that extracellular Tβ4 can stimulate differentiation of mesodermal progenitor cells to a mature mural cell fate through activation of the TGFβ pathway and that reduced TGFβ signalling correlates with the severity of haemorrhagic phenotype in Tβ4-null vasculature.Conclusions
We conclude that Tβ4 is a novel endothelial secreted trophic factor which functions upstream of TGFβ to regulate mural cell development and maintain aortic form and function into adulthood. These findings have important implications for understanding congenital anomalies that may be causative for adult-onset vascular instability as a progressive form of aneurysmal disease.