Prostaglandin E2 receptor EP4 signaling in vascular smooth muscle cells decreases aortic elasticity (1123.2)

Abstract

Arterial elasticity was impaired in advancing aortic aneurysm (AA). Since we have reported that the PGE2 receptor EP4 signaling was involved in progression of AA, we further examined whether EP4 signaling in smooth muscle cells (SMCs) decreases aortic elasticity. We generated mice (EP4TG) with vascular smooth muscle‐specific overexpression of human EP4 (hEP4). hEP4 mRNA was over‐expressed in the aorta of EP4TG (n=8). Using a wire myograph, we found that vasodilative effect of EP4 agonist (10 µM) was greater in the aortae of EP4TG than those of non‐transgenic mice (non‐TG) (25.0±2.9 vs. 9.6±2.0% of phenylephrine‐induced contraction, p<0.01, n=4‐6). Under basal conditions, aortic diameter and elasticity were not different. However, pressure‐induced dilation (20 to 220mmHg) was decreased in EP4TG than in non‐TG (0.84±0.04‐fold, n=5‐6, p<0.05). After angiotensin II (ATII) infusion (3.0µg/kg/min for 28 days), the aortae of EP4TG were enlarged to a greater degree than those of non‐TG (1.1±0.02‐fold, n=5‐6, p<0.05). A zelatin zymography revealed that MMP‐2 activity is higher in the aortae of EP4TG than in that of non‐TG (1.7±0.07‐fold, n=5, p<0.05). After ATII treatment, enhancement of MMP‐9 activation was greater in EP4TG than in non‐TG (1.6±0.19‐fold, n=5, p<0.05). These data suggest that EP4 signaling in SMCs decreases aortic elasticity by increasing MMP activation.