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Am J Physiol Heart Circ Physiol 278: H60-H66, 2000;
0363-6135/00 $5.00
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Vol. 278, Issue 1, H60-H66, January 2000

Regulation of endothelial nitric oxide synthase by PGD2 in the developing choroid

Isabelle Dumont1,2, Pierre Hardy1, Krishna G. Peri1, Xin Hou1, Stéphane Molotchnikoff2, Daya R. Varma3, and Sylvain Chemtob1,3

1 Departments of Pediatrics, Ophthalmology, and Pharmacology, Research Center of Hôpital Sainte-Justine, Montreal H3T 1C5; 2 Faculty of Biological Sciences, University of Montreal, Montreal H3C 3J7; and 3 Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada H3G 1Y6

We investigated if prostaglandins might regulate the increased choroidal endothelial (e) nitric oxide synthase (NOS) expression in the perinate. Prostaglandins, eNOS mRNA, immunoreactive protein and activity, and nitrite [stable metabolite of nitric oxide (NO)] production were markedly higher in newborn (1 day old) than juvenile (6-8 wk old) pig choroid. Treatment of isolated newborn choroids with the prostaglandin synthase inhibitor ibuprofen for 24 h reduced eNOS mRNA and nitrite production to values in juveniles. This effect was equally observed with the PGD2 receptor (DP) blocker BW A868C and was prevented by cotreatment with PGD2 but not other prostaglandins; similar observations were made on NOS activity in vivo. PGD2 also increased eNOS expression on choroids of juveniles, and this effect was blocked by BW A868C. The manifestation of this upregulation of eNOS by PGD2 on the control of choroidal vasomotor response was tested by using NO-dependent vasorelaxants, ACh, bradykinin (Bk), and substance P (SP). ACh-, Bk-, and SP-elicited choroidal vasorelaxation was greater in saline-treated newborn than juvenile pigs. Ibuprofen (24 h) decreased ACh-, Bk-, and SP-evoked vasorelaxation in newborns, whereas PGD2 increased that in juveniles and prevented the ibuprofen-induced attenuated relaxation in newborns; infusion of Nomega -monomethyl-L-arginine in choroids of those animals treated with PGD2 reversed the augmented vasorelaxation to ACh, Bk, and SP. Finally, PGD2-induced upregulation of NOS in the perinate was also reflected by curtailed choroidal blood flow autoregulatory response to increased perfusion pressure. In conclusion, PGD2 exhibits a major role in upregulating eNOS expression and activity in the choroid, which in turn results in greater NO-mediated vasorelaxation; a new mechanism for eNOS regulation via DP is hereby disclosed. The relationship between PGD2 and eNOS in the developing subject provides an explanation for the interactive role of these two factors in the absent choroidal blood flow autoregulation in the perinate.

endothelial nitric oxide synthase; newborn


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