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Home > Vascular Annual Meeting > damrauer_atheroprotective_molecule

The Atheroprotective Molecule A20 Inhibits Post-Angioplasty Restenosis by Both Anti-Inflammatory and Anti-Angiogenic Pathways

Scott M. Damrauer^1,2, Mark D. Fisher¹, Salvatore T. Scali¹, Hiromi Wada¹, Cleide G. da Silva¹, Eva Csizmadia¹, Elizabeth R. Maccariello¹, Karam Moon¹, Jeffery J. Siracuse¹, Robert Bolash¹, William Aird¹, Soizic Daniel^1, Christiane Ferran.^1
1Beth Israel Deaconess Medical Center, Boston, Mass.;²Massachusetts General Hospital, Boston, Mass.

OBJECTIVES: Restenosis following open and precutaneous procedures represents a significant burden of disease among patients with arterio-occlusive disease. Vascular injury at the time of the original intervention leads to both angiogenic and inflammatory signaling that promotes endothelial cell (EC) and smooth muscle cell (SMC) migration and neointimal hyperplasia. We have previously shown that the atheroprotective protein A20 can prevent neo-intimal hyperplasia; here we investigate its effect on homing of EC and SMC progenitors and angiogenesis following balloon angioplasty.

METHODS: We performed carotid balloon angioplasty on Sprague Dawley (SD) rat recipients of a bone marrow transplant from green fluorescent SD rats; all cells of hematopoietic origin could be identified by fluorescent microscopy. Injured carotids were treated with adenovirally delivered A20 or galactosidase, or saline.

RESULTS: A20 decreased neointimal formation. Neointimal SMC were negative for GFP expression indicating that they did not derive from bone marrow progenitor cells. In contrast, 5-10% of EC in the lumen and vaso vasorum of control vessels displayed both GFP and CD31 fluorescence, indicating they were of hemangiopoietic origin. Less CD31-GFP positive cells were detected in the vasovasorum of A20 treated vessels. This was related to decreased neovascularization in the intima and adventitia of A20-treated vessels and correlated with decreased VEGF expression. In vitro, A20 interrupted VEGF-mediated phosphorylation of PKCII and ERK1/2, both required for EC migration and proliferation. Additionally, A20 treatment decreased migration of bone marrow derived monocytes/macrophages to injured vessels with lower numbers of ED-1 cells when compared to control vessels. This is likely associated with decreased cytokine production and inflammation within the vessel.

CONCLUSIONS: We propose that A20-based therapies, by combining anti-inflammatory and anti-angiogenic effects in EC, hold promise for the prevention and/or treatment of post-angioplasty restenosis.

AUTHOR DISCLOSURES: S.M. Damrauer, None; M.D. Fisher, None; S.T. Scali, None; H. Wada, None; C.G. da Silva, None; E. Csizmadia, None; E.R. Maccariello, None; K. Moon, None; J.J. Siracuse, None; R. Bolash, None; W. Aird, None; S. Daniel, None; C. Ferran, None.