Expression of versican V3 by arterial smooth muscle cells alters tGF{beta}-, EGF-, and NF{kappa}B-dependent signaling pathways, creating a microenvironment that resists monocyte adhesion [Molecular Bases of Disease]

April 9th, 2014 by Kang, I., Yoon, D. W., Braun, K. R., Wight, T. N.

Monocyte/macrophage accumulation plays a critical role during progression of cardiovascular diseases such as atherosclerosis. Our previous studies demonstrated that retrovirally-mediated expression of the versican V3 splice variant (V3) by arterial smooth muscle cells (ASMCs) decreases monocyte adhesion in vitro and macrophage accumulation in a model of lipid-induced neointimal formation in vivo. We now demonstrate that V3-expressing ASMCs resist monocyte adhesion by altering the composition of the microenvironment surrounding the cells by affecting multiple signaling pathways. Reduction of monocyte adhesion to V3-expressing ASMCs is due to the generation an ECM enriched in elastic fibers and depleted in hyaluronan, and reduction of the pro-inflammatory cell surface adhesion molecule VCAM1. Blocking these changes reverses the protective effect of V3 on monocyte adhesion. The enhanced elastogenesis induced by V3 expression is mediated by transforming growth factor β (TGFβ) signaling, whereas the reduction in hyaluronan cable formation induced by V3 expression is mediated by the blockade of epidermal growth factor receptor (EGFR) and nuclear factorκB (NFκB) activation pathways. In addition, expression of V3 by ASMCs induced a marked decrease in NFκB-responsive pro-inflammatory cell surface molecules that mediate monocyte adhesion, such as vascular cell adhesion molecule 1 (VCAM1). Overall, these results indicate that V3 expression by ASMCs creates a microenvironment resistant to monocyte adhesion via differentially regulating multiple signaling pathways.
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