Endogenous prostaglandin E2 accelerates healing of indomethacin-induced small intestinal lesions through upregulation of vascular endothelial growth factor expression by activation of EP4 receptors.
OBJECTIVE
The effects of an EP4 agonist/antagonist on the healing of lesions produced by indomethacin in the small intestine were examined in rats, especially in relation to the expression of vascular endothelial growth factor (VEGF) and angiogenesis.


METHODS
Animals were given indomethacin (10 mg/kg s.c.) and killed at various time points. To impair the healing of these lesions, a small dose of indomethacin (2 mg/kg p.o.) or AE3-208 (EP4 antagonist: 3 mg/kg i.p.) was given once daily for 6 days after the ulceration was induced, with or without the co-administration of AE1-329 (EP4 agonist: 0.1 mg/kg i.p.).


RESULTS
Indomethacin (10 mg/kg) caused severe damage in the small intestine, but the lesions healed rapidly decreasing to approximately one-fifth of their initial size within 7 days. The healing process was significantly impaired by indomethacin (2 mg/kg) given once daily for 6 days after the ulceration. This effect of indomethacin was mimicked by the EP4 antagonist and reversed by co-administration of the EP4 agonist. Mucosal VEGF expression was upregulated after the ulceration, reaching a peak on day 3 followed by a decrease. The changes in VEGF expression paralleled those in mucosal cyclooxygenase-2 expression, as well as prostaglandin E(2) (PGE(2)) content. Indomethacin (2 mg/kg) downregulated both VEGF expression and angiogenesis in the mucosa during the healing process, and these effects were significantly reversed by co-treatment with the EP4 agonist.


CONCLUSIONS
The results suggest that endogenous PGE(2) promotes the healing of small intestinal lesions by stimulating angiogenesis through the upregulation of VEGF expression mediated by the activation of EP4 receptors.
Takeuchi
Koji
K
Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan. takeuchi@mb.kyoto-phu.ac.jp
Tanigami
Mayu
M
Amagase
Kikuko
K
Ochi
Akimu
A
Okuda
Sayaka
S
Hatazawa
Ryo
R
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000818:Animals; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D007213:Indomethacin; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010437:Peptic Ulcer / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010654:Phenylbutyrates / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D012720:Severity of Illness Index; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects
C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D008565:Membrane Proteins; D009281:Naphthalenes; D010654:Phenylbutyrates; C545652:Ptger4 protein, rat; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D015232:Dinoprostone; D015064:16,16-Dimethylprostaglandin E2; D007213:Indomethacin