Interaction of Monocytes With Vascular Smooth Muscle Cells Regulates Monocyte Survival and Differentiation Through Distinct Pathways

Abstract

Objective-Vascular smooth muscle cells (VSMCs) may regulate monocyte functions within atherosclerotic lesions. We investigated the impact of VSMC/monocyte interactions on monocyte apoptosis and scavenger receptor CD36 expression, key events related to monocyte survival and differentiation. Methods and Results-Serum deprivation significantly increased THP-1 and human peripheral blood monocyte apoptosis.However, this was significantly reversed by physical binding to human VSMCs (HVSMCs). On binding to HVSMCs, antiapoptotic kinase Akt and its downstream targets were phosphorylated, and Bcl-2 expression was enhanced.Binding-mediated suppression of apoptosis and Akt phosphorylation were attenuated by a phosphoinositide 3-kinase inhibitor and also by an antibody to vascular cell adhesion molecule-1. CD36 expression was also significantly increased in THP-1 cells and in human peripheral blood monocytes after binding to HVSMCs, and this was mediated by both direct contact and soluble factors. Extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase phosphorylation was increased in THP-1 cells after HVSMC coculture. Furthermore, an ERK1/2 inhibitor blocked monocyte CD36 upregulation. Contact-dependent CD36 induction and ERK1/2 phosphorylation in monocytes were inhibited by blocking vascular cell adhesion molecule-1 on HVSMC, whereas soluble factor-induced CD36 expression was attenuated by a monocyte chemoattractant protein-1 neutralizing antibody. I n response to atherogenic stimuli, monocytes in circulation adhere and migrate across the endothelium to the intimal space where they differentiate, take up lipid, and form foam cells. The role of vascular endothelial cells in the recruitment of monocytes during early steps of atherosclerosis has been well studied. [1][2][3] However, these initial processes may be reversible and do not cause clinical consequences. 1,2 It is the subsequent prolonged intimal retention of monocyte/macrophage and foam cell formation that are central features of atherogenesis. 1,2 However, the mechanisms by which monocytes/macrophages are retained within the vessel wall, survive, and differentiate to foam cells are not well documented. Once they transmigrate into the subendothelial intimal space, these monocyte functions are regulated mainly by the influence of local factors that are not well characterized. Furthermore, very little is known about the role of intimal vascular smooth muscle cells (VSMCs) in regulating subendothelial monocyte functions. Conclusions-TheseVSMC migration and proliferation are also welldocumented hallmarks of early atherosclerotic lesions. 1,4 Accumulating evidence suggests that interactions between transmigrated monocytes and VSMCs may contribute to monocyte retention and function within the vasculature. First, the potential of VSMCs to interact with monocytes is suggested by the fact that VSMCs express adhesion molecules within atherosclerotic lesions but not in the normal vascular wall. 5 A highly significant association was found between V...

Enhanced Proatherogenic Responses in Macrophages and Vascular Smooth Muscle Cells Derived From Diabetic db/db Mice

“…These cytokines/chemokines are involved in VSMC proliferation and migration and can also attract monocytes to bind to VSMCs. As recently shown, monocyte adhesion to VSMCs may be an important event in leading to monocyte retention, differentiation, and foam cell formation within the subendothelial space (26,44). Our results also showed that key signals involved in VSMC proliferation and migration are enhanced in db/db VSMCs.…”

“…Activation of VSMCs plays an important role in the development of atherosclerosis. Furthermore, because monocyte to macrophage transitions take place in the subendothelial space, VSMCs and monocyte/macrophages may cooperate to augment diabetic vascular dysfunction (26,44). Hence, we next examined inflammatory gene expression in aortic VSMCs isolated from db/ϩ and db/db mice.…”

“…Enhanced binding of monocytes to db/db VSMCs. We next examined whether the increased inflammatory chemokine gene expression observed in the db/db MVSMCs can lead to enhanced adhesion of monocytes because evidence shows that heterotypic interactions between these cell types may enhance monocyte to macrophage differentiation (44). Adhesion assays with WEHI mouse monocytes and MVSMCs were carried out as described earlier (26,44) and in RESEARCH DESIGN AND METHODS.…”

Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms

“…Recent evidence in both humans and experimental animal models of atherosclerosis suggests that SMCs within atherosclerotic plaques can express a number of proinflammatory genes such as vascular cell adhesion molecule 1 (Vcam1) (56), intercellular adhesion molecule 1 (Icam1) (60,61), chemokine (C-X-C motif) ligand 12 (Cxcl12) (1), chemokine (C-X3-C) motif ligand 1 (Cx3cl1) (44), and granulocyte macrophage colony stimulating factor (Gmcsf) (59). In vitro evidence demonstrates that production of VCAM1, ICAM1, and CX3CL1 by SMCs promotes adhesion of monocytes to SMCs as well as enhanced monocyte survival and activation (8,48,51), suggesting that expression of these proinflammatory genes by SMCs within plaques may contribute to formation of an inflammatory, unstable plaque phenotype (36). It is unclear, however, how or if inflammatory gene expression by plaque SMCs relates to the classical definition of SMC phenotypic modulation from a contractile to a synthetic state including repression of SMC differentiation marker genes and increased proliferation, migration, and matrix synthesis.…”

Activation of Thromboxane Receptor Upregulates Interleukin (IL)-1β–Induced VCAM-1 Expression Through JNK Signaling

“…Together with other adhesion molecules and chemoattractants VCAM-1 mediates leukocyte adhesion to the endothelial cells and infiltration of the neointima. [15][16][17] However, the interrelationship between TPr activation and the inflammatory response mediated by cytokines such as IL-1␤ has not been studied in aortic smooth muscle cells (VSMCs), and the mechanism by which blockade of TPr attenuates VCAM-1 expression is unknown. The present study aimed to determine how activation of the TPr with an agonist, U46619, enhances the expression of VCAM-1 induced by IL-1␤ in cultured VSMCs.…”