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1 Gonda Diabetes Center, Beckman Research Institute of City of Hope, Duarte, CA, USA
* To whom correspondence should be addressed. E-mail: rnatarajan{at}coh.org.
Adhesive interactions between monocytes and vascular smooth muscle cells (VSMC) may contribute to subendothelial monocyte/macrophage retention in atherosclerosis. We investigated the effects of angiotensin II (Ang II) and platelet-derived growth factor-BB (PDGF-BB) on VSMC/monocyte interactions. Treatment of human aortic VSMC (HVSMC) with Ang II or PDGF-BB significantly increased binding to human monocytic THP-1 cells and to peripheral blood monocytes. This was inhibited by antibodies to monocyte 
1 and 2 integrins. The binding was also attenuated by blocking VSMC arachidonic acid (AA) metabolism by inhibitors of 12/15-lipoxygenase (12/15-LO) or cyclooxygenase-2 (COX-2). Conversely, binding was enhanced by overexpression of 12/15-LO or COX-2. Direct treatment of HVSMC with AA or its metabolites also increased binding. Furthermore, VSMC derived from 12/15-LO knock-out mice displayed reduced binding to mouse monocytic cells relative to genetic control mice. Using specific signal transduction inhibitors, we demonstrated the involvement of Src, phosphoinositide-3-kinase and MAPKs in Ang II or PDGF-BB-induced binding. Interestingly, after co-culture with HVSMC, THP-1 cell surface expression of the scavenger receptor CD36 was increased. These results show for the first time that growth factors may play additional roles in atherosclerosis by increasing monocyte binding to VSMC via AA metabolism and key signaling pathways. This can lead to monocyte subendothelial retention, CD36 expression and foam cell formation.
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