Essential Role for Thymosin β4 in Regulating Vascular Smooth Muscle Cell Development and Vessel Wall Stability

Abstract

Rationale: Compromised development of blood vessel walls leads to vascular instability that may predispose to aneurysm with risk of rupture and lethal hemorrhage. There is currently a lack of insight into developmental insults that 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 ␤4 (T␤4), previously shown to be proangiogenic, in mural cell development and vascular wall stability. Methods and Results:Phenotypic analyses of both global and endothelial-specific loss-of-function T␤4 mouse models revealed a proportion of T␤4-null embryos with vascular hemorrhage coincident with a reduction in smooth muscle cell coverage of their developing vessels. Mechanistic studies revealed that extracellular T␤4 can stimulate differentiation of mesodermal progenitor cells to a mature mural cell phenotype through activation of the transforming growth factor-beta (TGF␤) pathway and that reduced TGF␤ signaling correlates with the severity of hemorrhagic phenotype in T␤4-null vasculature.Conclusions: T␤4 is a novel endothelial secreted trophic factor that functions synergistically with TGF␤ 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. (Circ Res. 2012; 111:e89-e102.) Key Words: thymosin Ⅲ vasculature Ⅲ mural cell Ⅲ aorta Ⅲ mouse Ⅲ mouse mutants Ⅲ smooth muscle differentiation Ⅲ vascular biology Ⅲ vascular smooth muscle T he development of a functional vasculature is an essential process during embryogenesis, perturbations in which result in fetal lethality or vascular disease after birth. The formation of systemic blood vessels occurs in a stereotypical fashion -endothelial tubes form through a number of mechanisms (angiogenesis, vasculogenesis, or intussusception). 1 Endothelial cells then recruit mural cells comprising the subsets of vascular smooth muscle cells (VSMCs) and pericytes to the external wall of the vessel. [2][3][4] These mural cells are required to provide structural support for the blood vessel and probably play a role in maintaining endothelial health and integrity. The establishment of a vessel wall is accomplished either through the differentiation of de novo mural cells from precursor populations or recruitment from a proliferating pool of mature cells. The former is thought to occur chiefly through the actions of endothelial secreted transforming growth factor-beta (TGF␤) and the latter through paracrine platelet-derived growth factor-B (PDGF-B). 4 Typically, in the embryo, mural cells originate from the in situ differentiation of mesodermal tissues, which surround endothelial tubes. 3,5 The exception to this is in the central nervous system, where blood vessels recruit to their outer layer via the migration of neurectodermal-derived mature mural cells, as typified by the development of the postnatal retinal vasc...

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Impairment in the number and function of CD34+/KDR+ circulating cells in diabetes and obesity with functional improvement after thymosin β4 treatment

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