REGULATION OF PROSTAGLANDIN-H-SYNTHASE-2 EXPRESSION IN CEREBROMICROVASCULAR SMOOTH-MUSCLE BY SERUM AND EPIDERMAL GROWTH-FACTOR

Growth factors may play a role in the formation of prostaglandins (PG) by cerebral blood vessels during development or reaction to injury. I n smooth muscle cultures isolated from murine cerebral microvessels PG production was induced with either serum or epidermal growth factor ( EGF). Prostaglandin H synthase (PGHS) activity peaked at 6 h after the addition oi 10% serum or 50 ng/ml EGF. Increases in expression of PGH S-1 mRNA were small (7- to 10-fold) compared with PGHS-2 (30- to 120-f old), and the induction patterns were different for serum and EGF. An increase in PGHS-2 message was detected by 0.5 h of adding either agen t, but peak induction occurred earlier for EGF than for serum, 1 h vs. 3 h, respectively. The response to either stimulus had returned to pr estimulation levels by 12 h. The induction of PGHS-2 protein was also transient, but followed a more delayed time course (peak levels at 6 h ). Induction of activity, message, and protein by either agent was blo cked by 1 mu M dexamethasone and attenuated by genistein (100 mu M), a nonspecific tyrosine kinase inhibitor. Tyrphostin 47, a more selectiv e EGF receptor tyrosine kinase inhibitor, dose-dependently inhibited E GF-stimulated PGHS activity, completely abolishing PG production at 10 0 mu M. However, this inhibitor had no effect on serum-stimulated PG p roduction. Curiously, 100 mu M tyrphostin 47 enhanced EGF-induced PGHS -2 mRNA and protein expression. These data suggest that ECF induces th e expression of PGHS-2 in cerebromicrovascular smooth muscle by a mech anism that requires tyrosine kinase activity and that is distinct from serum. Cell. Physiol. 176:495-505, 1998. (C) 1998 Wiley-Liss, Inc.