Published online before print February 21, 2002, doi: 10.1161/01.RES.0000013303.17964.7A
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Submitted on May 30, 2001
Revised on January 24, 2002
Accepted on February 6, 2002
Regulation of eNOS Expression in Brain Endothelial Cells by Perinuclear EP3 Receptors
Fernand Gobeil Jr ;
From the Departments of Pediatrics, Ophthalmology, and Pharmacology (F.G., I.D., A.M.M., A.V.-T., S.G.B., D.A., X.H., M.H.B., C.Q., A.B., M.B., S.C.), Research Center of Hôpital Sainte-Justine, Montréal; the Faculty of Biological Sciences (I.D., S.M.), Université de Montréal; the Department of Pharmacology and Therapeutics (A.M.M., M.B., A.R.-d.-S., D.R.V., S.C.), McGill University, Montréal, Québec, Canada; and the Department of Cellular Biology (S.C., G.B.), Université de Sherbrooke, Sherbrooke, Québec, Canada.
* To whom correspondence should be addressed. E-mail: sylvain.chemtob{at}umontreal.ca.
We reported upregulation of endothelial nitric oxide synthase (eNOS) by PGE2 in tissues and presence of perinuclear PGE2 receptors (EP). We presently studied mechanisms by which PGE2 induces eNOS expression in cerebral microvessel endothelial cells (ECs). 16,16-Dimethyl PGE2 and selective EP3 receptor agonist M&B28767 increased eNOS expression in ECs and the NO-dependent vasorelaxant responses induced by substance P on cerebral microvessels. These effects could be prevented by prostaglandin transporter blocker bromcresol green and actinomycin D. EP3 immunoreactivity was confirmed on plasma and perinuclear membrane of ECs. M&B28767 increased eNOS RNA expression in EC nuclei, and this effect was augmented by overexpression of EP3 receptors. M&B28767 also induced increased phosphorylation of Erk-1/2 and Akt, as well as changes in membrane potential revealed by the potentiometric fluorescent dye RH421, which were prevented by iberiotoxin; perinuclear KCa channels were detected, and their functionality corroborated by NS1619-induced Ca2+ signals and nuclear membrane potential changes. Moreover, pertussis toxin, Ca2+ chelator, and channel blockers EGTA, BAPTA, and SK&F96365, as well as KCa channel blocker iberiotoxin, protein-kinase inhibitors wortmannin and PD 98059, and NF-
B inhibitor pyrrolidine dithiocarbamate prevented M&B28767-induced increase in Ca2+ transients and/or eNOS expression in EC nuclei. We describe for the first time that PGE2 through its access into cell by prostaglandin transporters induces eNOS expression by activating perinuclear EP3 receptors coupled to pertussis toxin--sensitive G proteins, a process that depends on nuclear envelope KCa channels, protein kinases, and NF-B; the roles for nuclear EP3 receptors seem different from those on plasma membrane.
Key words: perinuclear EP3 receptor • prostaglandin E2 • transporter • nitric oxide synthase • potassium channels • protein kinases
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