Abstract 476: Glucagon Like Peptide -1 Receptor Activation Does Not Affect Re-endothelialization But Reduces Intimal Hyperplasia via Direct Effects on Smooth Muscle Cells in a Non-diabetic Model of Arterial Injury

Abstract

Background/Aims: Diabetic patients have an increased risk of restenosis and late stent thrombosis after angioplasty, complications that are related to a defective re-endothelialization. Exendin-4, a stable GLP-1 receptor agonist has been suggested to influence the formation of intimal hyperplasia and to increase endothelial cell proliferation in vitro. Thus, the aim of the study was to investigate the mechanisms by which treatment with exendin-4 could influence re-endothelialization and intimal hyperplasia after vascular injury. Methods: 40 male Sprague-Dawley rats were subjected to balloon injury of the left common carotid artery (LCCA) and treated for four weeks with exendin-4 (1 nmol/day) or vehicle. Intimal hyperplasia and vessel wall elasticity were monitored non-invasively by high frequency ultrasound and re-endothelialization was evaluated upon sacrifice using Evans blue dye. The LCCA was then sectioned for subsequent morphometric and immunohistochemical analyses. To further investigate if and how smooth muscle cells (SMCs) are directly affected by exendin-4 treatment, we studied proliferation and apoptosis of SMCs in vitro. Results and Conclusion: Exendin-4 selectively reduced proliferation of SMCs and intimal hyperplasia in vivo without affecting the re-endothelialization process, however treatment with exendin-4 improved arterial wall elasticity. Our data also show that exendin-4 significantly decreased the proliferation and increased the apoptosis of SMCs in vitro, effects that appear to be mediated through cAMP signaling and endothelial nitric oxide synthase following GLP-1 receptor activation. Together, these effects of exendin-4 are highly desirable and may lead to improved outcome for patients undergoing vascular interventions.