Diabetic conditions act as matchmaker for monocytes and vascular smooth muscle cells.

LIFESTYLE FACTORS, together with genetic predisposition, contribute to the current rapid growth in number of patients with diabetes mellitus. This has resulted in a dramatic increase in patients with cardiovascular disease, given that diabetes is a major risk factor for the development of atherosclerosis (1). Understanding the molecular and cellular mechanisms that lead to the development of atherosclerosis is critical for the identification of strategies to limit the progression of this disease before it has clinical consequences. Published studies have revealed that many different cell types, including monocytes/ macrophages, lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs), are involved in atherogenesis (12, 13, 16, 18). Monocytes/macrophages play key roles at all stages of atherosclerosis (12, 18). In response to atherogenic stimuli, monocytes located within the circulation adhere to, and migrate across, the endothelium. These initial processes may be reversible, whereas the subsequent prolonged intimal retention of monocytes/macrophages and formation of foam cells represent a central pathogenic process in atherogenesis (12, 18). Atherosclerotic lesions in patients with diabetes are characterized by excessive macrophage/foam-cell infiltration (compared with those from nondiabetic individuals), suggesting that the recruitment of monocytes to the vessel wall may be augmented under diabetic conditions (15). However, the precise mechanisms by which monocytes/macrophages are retained within the vessel wall, survive, and differentiate into foam cells are not well documented as far as diabetic conditions are concerned. VSMC migration and proliferation and inflammatory gene expression are also well-documented events in atherosclerosis (6), and diabetic conditions have been shown to enhance these processes (16). Although ECs are thought to be the major cell type responsible for interacting with macrophages, increasing evidence suggests that adhesive interactions between migrated monocytes and VSMCs may contribute to monocyte-macrophage retention within the vasculature (6). The potential of VSMCs to interact with monocytes is indicated by the finding that VSMCs express adhesion molecules within atherosclerotic lesions but not in normal vessels (2). Indeed, direct contact between VSMCs and macrophages has been detected within human atherosclerotic plaques by electron microscopic and immunohistochemical analyses (20). However, the mechanisms by which the subendothelial retention of monocytes occurs under diabetic conditions, and the role played by VSMCs in this process, remain unclear. In this issue of American Journal of Physiology-Heart and Circulatory Physiology, a study performed in Natarajan’s laboratory [Meng et al. (14)] is reported in which that group addressed the effects of diabetic conditions on the binding of monocytes to VSMC, and their subsequent differentiation, using in vitro, ex vivo, and in vivo methods. Hyperglycemia and the subsequent formation of advanced glycation end products (AGEs) are recognized as essential mediators in the pathogenesis of diabetic vasculopathy (4). Diabetogenic conditions such as high glucose (HG) and activation of AGEs/ RAGE (receptor for AGEs) enhance inflammatory gene expression and proatherogenic responses in VSMCs (9, 16). In one set of experiments, these authors (14) found that human aortic VSMCs (HVSMCs) treated with diabetic stimuli such as HG or S100B, a ligand of RAGE (19), exhibited enhanced binding of human THP-1 monocytic cells. Moreover, these diabetic stimuli increased the expression of the adhesive chemokine fractalkaline (FKN) in HVSMCs. Previously, it was recognized that FKN and monocyte chemoattractant protein (MCP-1) are important chemokines, since they serve as mediators of the interaction between monocytes and ECs or VSMCs, and also that they play distinct roles in the development of atherosclerosis (3). Natarajan’s group (14) have now demonstrated that pretreatment of HVSMCs with neutralizing antibodies to FKN or MCP-1 significantly inhibited monocyteVSMC binding, whereas monocytes treated with FKN exhibited enhanced binding to VSMC. Against the above background, these new findings strongly suggest that in diabetic conditions, there is enhanced monocyte-VSMC binding and that this enhancement is related to the presence of increased levels of certain chemokines (i.e., FKN and MCP-1). This is supported by reports showing 1) that AGEs and S100B can increase MCP-1 expression in cultured VSMCs (9, 17) and 2) that HG conditions induce upregulations of FKN and MCP-1 in VSMCs (7). Meng et al. (14) further investigated whether monocyte binding might be enhanced in mouse VSMCs (MVSMCs) isolated from db/db mice, a well-established model of type 2 diabetes. In a previous report by Natarajan’s group (11), short-term ex vivo cultures of MVSMCs isolated from db/db mice displayed enhanced proinflammatory responses, including MCP-1 expression and monocyte binding. In the new study (14), MVSMCs isolated from diabetic db/db mice (vs. nondiabetic control db/ mice) were found to exhibit enhanced monocyte binding and increased FKN expression. Furthermore, pretreatment of db/db MVSMCs with neutralizing antibodies to MCP-1 or FKN attenuated the enhanced monocyte/ MVSMC binding. For a better indication of the possible in vivo significance, Meng et al. (14) investigated the interaction between monocytes and VSMCs using endotheliumdenuded aortas, with an exposed VSMC layer, isolated from Address for reprint requests and other correspondence: K. Kamata, Dept. of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi Univ., Shinagawa-ku, Tokyo 142-8501, Japan (e-mail: [email protected]). Am J Physiol Heart Circ Physiol 298: H731–H733, 2010; doi:10.1152/ajpheart.01157.2009. Editorial Focus