Abstract 5556: Apelin Regulates Vascular Remodeling In The Mouse Carotid Artery Ligation Model
Background: Apelin and its cognate G-protein coupled receptor APJ constitute a signaling pathway with numerous effects on the cardiovascular system. To investigate the hypothesis that apelin can modulate vascular remodeling, we employed the carotid ligation model in apelin knockout (apelin-KO) and wildtype (WT) control mice.
Methods and Results: The common carotid artery was ligated proximal to the bifurcation, and after 4 weeks, the carotid arteries were harvested, and histological analysis and real time PCR was performed. While APJ expression was barely detectable in normal carotid artery in both genotypes, APJ mRNA levels were upregulated by 10-fold in the ligated artery compared to non-ligated artery. In situ analysis showed increased APJ mRNA primarily in the adventitia, and some increased expression in the neointima and media. Neointimal lesion area (3.33±1.04 vs. 1.17±0.17 mm2, p=0.02) and I/M ratio (1.49±0.44 vs. 0.81±0.23, p=0.03) were significantly decreased in apelin-KO compared with WT mice. The ratio of total vessel areas, ligated arteries compared to controls, was smaller in apelin-KO (0.68±0.06 vs. 0.55±0.09, p=0.07), indicating that negative remodeling was increased, but did not statistically significant. The smooth muscle positive area in the neointima was decreased in apelin-KO mice, and P47-phox and TGF-beta mRNA levels in the ligated arteries were lower in apelin-KO compared to WT mice, suggesting a primary role for apelin in the smooth muscle response to injury. In vitro experiments with cultured rat aortic smooth muscle cells revealed that H2O2 stimulation increased APJ expression, and apelin stimulation increased migration in the Boyden chamber assay in a dose dependent manner.
Conclusion: Apelin-APJ signaling supports neointimal formation in the mouse carotid ligation model, with increased smooth muscle cell migration and proliferation providing the likely mechanism for this effect.