Abstract 3371: EP2 Receptor Signaling Effects the Early Phase of Collateral Remodeling During Ischemic Hindlimb Conditions in the Rat and in The EP2 Receptor Knockout Mouse
Tissue ischemia induced by coronary or peripheral artery disease is the foremost cause of reduced quality of life, morbidity and mortality in the industrialized society. Collateral development is physiologically the most relevant process to restore of perfusion to ischemic beds. However, the biology of collateral growth is still poorly understood. Previous profiling studies of collateral tissues isolated from multiple stages of hindlimb ischemia in rats provided strongly induced transient expression profiles of prostaglandin members including the EP2 receptor during the first 3 days of collateral development. The present study focused on the effects of EP2 receptor stimulation and inhibition during collateral growth. Collateral development was investigated in ischemic hindlimbs of EP2 knockout mice (EP2−/−) and in Sprague Dawley rats treated with an EP2 receptor specific agonist (till 5 days post-operative). Laser Doppler and CT analysis were performed to determine perfusion recovery and collateral growth. EP2 wild type (WT) mice and non-treated rats showed a typical fast perfusion recovery of the occluded hindlimb up to 40% during the first week post-operative. With 36.1+/−3.5% WT vs. 11.6+/−4.6% EP2−/− at day 1 and 39.7+/−3.7% WT vs. 27.03+/−4.4% EP2−/− at day 3, the EP2−/− mice revealed significant (n=6, p<0.05) depressed perfusion rates for the first phase of recovery. Stimulation with the specific EP2 agonist in rats showed the opposite effect with an increased recovery rate during the first phase being significantly different (n=8, p<0.05) for day 1 (50.8+/−1.3% WT vs 20%+/−5.3% EP2−/−) and day 3 (54.5+/−6.8% WT vs 26.01+/−8.1%). From our data we can conclude that EP2 receptor signaling is positively involved in the initial phase of collateral growth, which is compatible with the notion that innate immune responses are instrumental in the early stages of this revascularization process.