Expression of versican V3 by arterial smooth muscle cells alters tumor growth factor β (TGFβ)-, epidermal growth factor (EGF)-, and nuclear factor κB (NFκB)-dependent signaling pathways, creating a microenvironment that resists monocyte adhesion.
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 of an extracellular matrix enriched in elastic fibers and depleted in hyaluronan, and reduction of the proinflammatory cell surface vascular cell adhesion molecule 1 (VCAM1). Blocking these changes reverses the protective effect of V3 on monocyte adhesion. The enhanced elastogenesis induced by V3 expression is mediated by TGFβ signaling, whereas the reduction in hyaluronan cable formation induced by V3 expression is mediated by the blockade of epidermal growth factor receptor and NFκB activation pathways. In addition, expression of V3 by ASMCs induced a marked decrease in NFκB-responsive proinflammatory cell surface molecules that mediate monocyte adhesion, such as VCAM1. Overall, these results indicate that V3 expression by ASMCs creates a microenvironment resistant to monocyte adhesion via differentially regulating multiple signaling pathways.
From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101.
Inkyung
I
Kang
From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101.
Dong Won
DW
Yoon
From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101.
Kathleen R
KR
Braun
From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101 twight@benaroyaresearch.org.
Thomas N
TN
Wight
D000818:Animals; D002448:Cell Adhesion / Q000276:immunology*; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000276:immunology; D004815:Epidermal Growth Factor / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D053675:Versicans / Q000276:immunology / Q000378:metabolism*
D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; C508324:Vcan protein, rat; D053675:Versicans; D004815:Epidermal Growth Factor
Elastin; Epidermal Growth Factor Receptor (EGFR); Extracellular Matrix; Hyaluronate; Monocytes; NFkappaB; Transforming Growth Factor Beta (TGFbeta); Vascular Smooth Muscle Cells; Versican