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(Circulation Research. 2002;90:682.)
© 2002 American Heart Association, Inc.

Cellular Biology

Regulation of eNOS Expression in Brain Endothelial Cells by Perinuclear EP₃ Receptors

Fernand Gobeil, Jr, Isabelle Dumont, Anne Marilise Marrache, Alejandro Vazquez-Tello, Sylvie G. Bernier, Daniel Abran, Xin Hou, Martin H. Beauchamp, Christiane Quiniou, Asmaa Bouayad, Sanaa Choufani, Mousumi Bhattacharya, Stephane Molotchnikoff, Alfredo Ribeiro-da-Silva, Daya R. Varma, Ghassan Bkaily, Sylvain Chemtob

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.

Correspondence to Dr Sylvain Chemtob, MD, PhD, Research Center, Hôpital Sainte-Justine, Depts of Pediatrics, Ophthalmology and Pharmacology, 3175, Côte Sainte-Catherine, Montréal, Quebec, Canada, H3T 1C5. 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 K_Ca 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 K_Ca 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 K_Ca 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

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