Prostaglandin E receptor EP4 stimulates lymphangiogenesis to promote mucosal healing during DSS-induced colitis

Abstract

In the intestine, the formation of new lymphatic vessels from pre-existing lymphatic vasculature (lymphangiogenesis) is related to the progression of inflammatory bowel disease (IBD). However, it remains unclear whether lymphangiogenesis contributes to mucosal repair after acute colitis. Prostaglandin E receptor EP4 suppresses the development of experimental colitis. In this study, we investigated whether EP4 exerts this effect by contributing to lymphangiogenesis, in turn promoting mucosal tissue repair, following acute colitis. We elicited experimental colitis in male C57/BL6 mice by administering dextran sulphate sodium (DSS) via the drinking water for 5 days, followed by normal water for 9 additional days. From Day 5 through Day 13, the experimental mice received a daily dose of EP4-selective agonist, EP4-selective antagonist, or vehicle. On Day 14, mice treated with vehicle had recovered 95 % of body weight and exhibited moderate increases in disease activity and histological score relative to untreated controls. Compared with vehicle, post-treatment with EP4 antagonist increased signs of colitis, colonic tissue destruction, and CD11b+ cell infiltration, associated with elevated lymphatic vessel density (LVD) and reduced percentage of lymphatic vessel area (LVA%). By contrast, post-treatment with EP4 agonist improved disease activity, suppressed CD11b+ infiltration, and decreased levels of inflammatory cytokines; these changes were associated with upregulation of lymphatic growth factors and lymphangiogenesis, as evidenced by increases in LVA% and lymphatic drainage function. Inhibition of vascular endothelial growth factor receptor 3 (VEGFR3) caused a delay in mucosal repair, accompanied by impaired lymphangiogenesis. These results suggest that EP4 stimulation aids in mucosal repair from DSS-induced acute colitis by promoting lymphangiogenesis.