We examined the involvement of
cyclooxygenase (COX)-1 as well as COX-2 in the healing of
gastric ulcers and investigated which
prostaglandin (PG) EP receptor subtype is responsible for the healing-promoting action of
PGE2. Male SD rats and C57BL/6 mice, including wild-type, COX-1(-/-), and COX-2(-/-), were used.
Gastric ulcers were produced by thermocauterization under
ether anesthesia.
Gastric ulcer healing was significantly delayed in both rats and mice by
indomethacin and
rofecoxib but not
SC-560 given for 14 days after ulceration. The impaired healing was also observed in COX-2(-/-) but not COX-1(-/-) mice. Mucosal
PGE2 content increased after ulceration, and this response was significantly suppressed by
indomethacin and
rofecoxib but not
SC-560. The delayed healing in mice caused by
indomethacin was significantly reversed by the coadministration of
11-deoxy-PGE1 (EP3/EP4 agonist) but not other
prostanoids, including the EP1, EP2, and EP3 agonists. By contrast,
CJ-42794 (selective EP(4) antagonist) significantly delayed the
ulcer healing in rats and mice.
VEGF expression and angiogenesis were both upregulated in the ulcerated mucosa, and these responses were suppressed by
indomethacin, rofocoxib, and
CJ-42794. The expression of
VEGF in primary rat gastric fibroblasts was increased by
PGE2 or AE1-329 (EP4 agonist), and these responses were both attenuated by coadministration of
CJ-42794. These results confirmed the importance of COX-2/
PGE2 in the healing mechanism of
gastric ulcers and further suggested that the healing-promoting action of
PGE2 is mediated by the activation of EP4 receptors and is associated with
VEGF expression.