Abstract 15247: Adenosine A2B Receptor Agonism Inhibits Vascular Smooth Muscle Cell Proliferation and Intimal Hyperplasia in ApoE Deficient Mice
The adenosine A2B receptor (A2BR) is highly expressed in macrophages and vascular smooth muscle cells (vSMC) and has been established as an important regulator of inflammation and vascular adhesion. Recently, it has been demonstrated that A2BR deficiency enhances neointimal lesion formation after injury. Therefore, we hypothesize that A2BR agonism may protect against injury-induced intimal hyperplasia. To test this hypothesis, nine week old female ApoE deficient mice were fed a Western-type diet for 1 week, after which the left common carotid artery was denuded using a guide wire. Mice (n=10 per group) were treated daily with either vehicle control or the A2BR agonist BAY 60–6583 (50 μg/mouse), leading to plasma concentrations of approximately 1 μg/mL at 2 hours after injection. After 18 days, mice were sacrificed and lesions analyzed. Interestingly, lumen stenosis as defined by the neointima/lumen ratio was inhibited by treatment with the A2BR agonist from 2.1 ± 0.3 in the controls to 1.3 ± 0.2 (P<0.05) in treated mice. Total vessel area remained unaffected (controls: 140 ± 8*103 μm2 versus BAY 60-6583: 131 ± 8*103 μm2, P=NS), demonstrating absence of outward remodeling. Collagen content was increased from 10.7 ± 1.9% in the control animals to 17.0 ± 2.0% in the BAY 60–6583 treated mice (P<0.05), while macrophage content was unchanged. To determine whether A2BR agonism affects vSMC proliferation, cultured murine vSMCs were stimulated with BAY 60–6583 for 24 hours, after which [3H]Thymidine incorporation was measured. We observed a dose-dependent reduction in vSMC proliferation from 240 ± 11*103 dpm to 111 ± 13*103 dpm at 1 μg/mL BAY 60–6583 and even up to 5 ± 2*103 dpm at a concentration of 10 μg/mL (both P<0.001). Within this concentration range BAY 60–6583 did not induce cell death. Furthermore, collagen production by cultured vSMCs as determined using a picrosirius red staining was increased by 20% and 50% at increasing BAY 60–6583 concentrations (P<0.05). In conclusion, our data show that activation of the adenosine A2B receptor protects against vascular injury, while also it also enhances plaque stability as indicated by increased collagen content. These outcomes thus point to A2B receptor agonism as a new therapeutic approach in the prevention of restenosis.
- © 2010 by American Heart Association, Inc.