P159	Angiopoietin-1 promotes adhesion of monocytes to vascular smooth muscle cells and increases plaque size in ApoE-/- mice.
1T.Fujisawa, 1R.Potluri, 2X.Niu, 1S.Ahmad, 1G.Molostvov, 1M.Cudmore, 3H.Kuramoto, 1P.Hewett, 2Chr.Kontos, 1A.Ahmed
1Reproductive and Vascular Biology, The Medical School, University of Birmingham, Birmingham, GB; 2Duke University Medical Center, Durham NC, US; 3Graduate School of Medical Sciences, Kitasato University, Kanagawa, JP.

Atherosclerosis is characterised by the accumulation of lipids and fibrous elements forming plaques in the large arteries. Intimal retention of monocytes/macrophages and foam cell formation is the central feature in atherogenesis and is regulated mainly by the influence of local factors. Very little is known about the role of intimal vascular smooth muscle cells (VSMCs) in regulating subendothelial monocyte functions or the role of the angiopoietins in this process. Immunohistochemical, RT-PCR, Western blot and FACS analysis revealed that human VSMCs express Tie2, the receptor for angiopoietin-1 (Ang1). Monocyte adhesion was significantly increased within 60 mins following stimulation of VSMCs for 6 hours with 20ng/ml PDGF (215“), 10ng/ml TNF-ƒ¿ (229%), 400ng/ml Ang1 (294%) or Ang2 (205%; p< 0.01 vs. control). Ang2 antagonised Ang1-induced monocyte adhesion, which was specific and Tie2 receptor-mediated as soluble Tie2 or Tie2 blocking antibody or anti-tie2 peptide inhibited it. Monocyte adhesion induced by Ang1 was also PI3-kinase dependent as the PI3-kinase inhibitor Ly294002 inhibited it in a dose-dependent manner. To further investigate the role of Ang1 on the development of early atherosclerosis, apoE-/- mice were fed a Western diet for 3 weeks then treated systemically with a control, empty adenovirus (AdEV) or adenovirus encoding Ang1 and maintained on a Western diet. Four weeks later, mice were sacrificed and atherosclerosis was quantified by oil red O staining of aortic sections. AdAng1 treatment significantly increased mean atherosclerotic lesion area by 57% compared to AdEV-treated mice (Ang1: 0.687 +/- 0.071 mm2; EV: 0.437 +/- 0.045 mm2; P<0.01). The findings demonstrate the expression of functional Tie-2 receptor in human VSMCs, which induces monocyte adhesion via the PI3-kinase pathway and which may relate to the increase in atherosclerosis seen in Ang1-treated apoE-/- mice. These finding may have important implications for targeting the angiopoietins in the treatment of ischemic, atherosclerotic vascular diseases.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.