Phenotypic regulation of vascular smooth muscle cell

Abstract

In response to vascular stress, vascular smooth muscle cells (VSMCs) specialized to contract can be induced to lose their contractile function and acquire synthetic functions including inflammation, proliferation and migration. In part I and II, I will describe the possible mechanism by which VSMCs increase the synthetic activity in response to treatment with cytokines and growth factor. Tumor necrosis factor-$\alpha$ (TNF-$\alpha$) and TNF-related apoptosis-inducing ligand (TRAIL) are best known for their selective cytotoxicity of transformed tumor cells. Recent studies revealed that most non-transformed primary cells and several cancer cell lines are not only resistant to death receptor-induced apoptosis, but also subject to pro-inflammatory responses in a NF-$\kappaB$-dependent manner. While involvement of these cytokines in a variety of vascular disorders has been proposed, the exact molecular mechanisms are unclear. In the present study, we aimed to delineate the role of TNF-$\alpha$ and TRAIL in VSMC proliferation. We also sought possible molecular mechanisms to identify potential targets for the prevention and treatment of post-angioplastic restenosis and atherosclerosis. We demonstrated that treatment with TNF-$\alpha$ and TRAIL increased intercellular adhesion molecule-1 expression in VSMCs via differential activation of PKC$\delta$ and subsequent generation of intracellular reactive oxygen species and NF-$\kappaB$ activation. Following detailed analysis using various PKC$\delta$ mutants, we determined that PKC$\delta$activation was mediated by caspase-dependent proteolysis upon TRAIL ligation, while phosphorylation was the main mechanism responsible for TNF-$\alpha$-induced signals. The pivotal role of PKC$\delta$ in vascular pathology was further confirmed by its protective effect on posttraumatic vascular remodeling after in vivo knockdown. These results collectively indicate the pivotal role of PKC$\delta$ in TNF-$\alpha$- and TRAIL-induced vasc...