Abstract 14446: Prostaglandin E2 Receptor EP4 Signaling in Vascular Smooth Muscle Decreased Elasticity of the Aorta
Introduction: Elasticity largely contributes to mechanical properties of the arteries and loss of elastic properties exacerbates aortic diseases, such as atherosclerosis or aortic aneurysms (AA). It is well known that prostaglandin E2 (PGE2) synthesis is enhanced in aortic diseases. We have demonstrated that the PGE2 receptor EP4 was abundantly expressed in smooth muscle cells (SMCs) from human AA tissues.
Hypothesis: We examined whether PGE2-EP4 signaling in SMCs decreases elasticity in the aorta.
Methods: We generated mice with vascular smooth muscle-specific overexpression of human EP4 using the Cre-loxP system (EP4loxP/-/SM22-Cre mice: EP4TG and EP4-/-/SM22-Cre mice: EP4NTG). Transcription profiles of the aorta were examined by quantitative RT-PCR and DNA microarray analyses. EP4 protein expression was examined by immunohistochemistry. Isometric tension of the aorta was measured using a wire myograph. Elasticity was evaluated by simultaneous measurement of dimension and pressure of the aorta under basal conditions or angiotensin II (ATII) systemic infusion (2.2μg/kg/min) for 14 days.
Results: We obtained two lines of EP4TG in which human EP4 mRNA was abundantly overexpressed in the aorta (n=8, respectively) and used one of them. Vasodilative effect of EP4 agonist (10 μM) was greater in the aorta of EP4TG than EP4NTG (25.0±2.9 vs. 7.9±2.1% of phenylephrine-induced contraction, p<0.01, n=4-6). Under the basal condition, aortic diameter and elasticity were not different between EP4TG and EP4NTG (n=4). After ATII infusion, however, the aorta of EP4TG were deformed and enlarged to a greater degree than that of EP4NTG (1.1±0.05-fold, n=3-4). Further, pressure-induced dilation (60 to 180mmHg) was decreased in EP4TG (0.74±0.04-fold, n=3-4). Microarray data showed that matrix metalloproteinase-9, which is known to degrade elastic fiber, was increased in EP4TG (1.7-fold, n=4, p<0.05), while expression levels of elastic fiber components, such as tropoelastin, fibrillin-1,-2, or lysyl oxidase were not changed.
Conclusions: EP4 signaling in SMCs is suggested to be decreased aortic elasticity by promoting the degradation of elastic fibers. Antagonizing PGE2-EP4 signaling may be beneficial for preventing progression of atherosclerosis or AA.
- © 2013 by American Heart Association, Inc.