Abstract 626: Myocyte Enhancer Factor 2A is a Potent Regulator of Angiogenesis and of Erythrocyte Extravasation in Atherosclerotic Plaques.
Background: The transcription factor myocyte enhancer factor 2A (MEF2A) was recently found to be expressed in vascular smooth muscle (VSMC) and endothelial cells. Furthermore, MEF2A polymorphisms were identified that imparted an increased risk for coronary artery disease and myocardial infarction, suggestive of a role of MEF2A in these disorders. This led us to investigate whether MEF2A does so by modulating atherogenesis and/or angiogenesis.
Methods and Results: Murine VSMC proliferation on Matrigel was 3.1-fold increased after infection with constitutively active MEF2A adenovirus (Ad-caMEF2A) compared to Ad-empty (P=0.007). Likewise, MEF2A overexpression markedly enhanced the proliferation of mouse hemangioma endothelial cells (41,700±9,118 vs. 11,400±2,789 DPM/mg for Ad-Empty treated cells; P=0.015). These findings were confirmed in vivo in a Matrigel plug assay, in that 1 week after s.c. injection of C57/Bl6 mice with Matrigel containing Ad-caMEF2A or Ad-empty, Ad-caMEF2A plugs (N=5) revealed a clear induction of neovessel formation compared to Ad-Empty plugs, as assessed by the number of infiltrating neovessels. Next, we have addressed the effect of vascular MEF2A activity modulation on plaque formation in Western type diet (0.25% cholesterol) diet fed apoE−/ − mice (n=34) using an model of collar-aided, flow induced carotid artery atherosclerosis. Four weeks after surgery, the resulting plaques were incubated transluminally on the left side with Ad-caMEF2A, Ad-dnMEF2A (dominant negative MEF2A) or Ad-empty and sham operated on the right side. After 17 days, mice were sacrificed and carotid artery plaques were analysed morphometrically and histologically. No differences were seen in plaque size, media size and percentage stenosis. Also, plaque morphology and composition remained unaffected as well. Interestingly however, more intraplaque haemorrhages were observed in the dnMEF2A versus sham treated groups (38 vs. 0% Perl’s iron positive plaques; P<0.01).
Conclusion: We are the first to show that MEF2A activation is highly mitogenic and proangiogenic to vascular wall cells in vitro and in vivo. Vascular modulation of MEF2A activity does however not lead to significant alterations in atherosclerotic plaque phenotype in vivo.