Mechanical Strain Enhances TGF-beta Responsiveness by Altering TGF-beta Receptor Partitioning Between Submembrane Microdomains in Vascular Smooth Muscle Cells

摘要

Vascularization is one of the great challenges that tissue engineering faces in order to achieve sizeable tissue and tissue substitutes that accommodate living cells. Mechanical force plays a crucial role in promoting the maturation of arterial vascular smooth muscle cells (VSMCs). However, the underlying molecular mechanisms remain elusive. Transforming growth factor (TGF-beta) is a crucial inducer of VSMC differentiation/maturation, and its responsiveness can be modulated through TGF-beta receptor partitioning between lipid raft/caveola-and clathrin-mediated endocytosis pathways. Lipid rafts/caveolae are unique membrane microdomains that play an important role in regulating signaling, mechanosensitivity, and adaptation to membrane tension. In this study, we investigated the role of mechanotransduction in TGF-beta signaling by using cultured VSMCs and Mv1Lu cells that were exposed to unidirectional stretch. TGF-beta receptors were predominantly localized in lipid raft/caveolar microdomains in nonstretched cells, and were translocated to noncaveolar microdomains after stretching. This phenomenon was associated with an increase in the ability of TGF-beta to induce Smad2 phosphorylation in stretched cells. This is the first mechanistic study to reveal that mechanical strain significantly enhanced TGF-beta-induced VSMC maturation, and our findings implicate a novel control mechanism in which arterial maturation caused by mechanical forces is controlled by raft and nonraft artitioning of TGF-beta receptors in the plasma membrane.