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Retinal Capillary Pericyte Proliferation and c-Fos mRNA Induction by Prostaglandin D₂ through the cAMP Response Element

From the Laboratories of ¹ Ocular Therapeutics and ² Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland; and the ³ Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma.

PURPOSE. Cycloxygenase inhibitors have been shown to prevent angiogenesis in some circumstances, suggesting that growth of capillary pericytes or endothelial cells may be regulated by prostaglandins (PGs). The present study tests the effects of PGs on the growth of human retinal capillary pericytes.

METHODS. Cell growth was assayed by formazan formation and 5-bromo-2'-deoxyuridine (BrdU) incorporation. The expression of mRNAs corresponding to c-fos, PG receptors, and VEGF was examined by RT-PCR. Signal transduction was evaluated by immunoblot analysis using phosphospecific antibodies against mitogen-activated protein kinases (MAPKs) and cAMP response element–binding protein (CREB). Synthesis of cAMP was inhibited with the adenyl cyclase inhibitor SQ22536. A reporter gene (luciferase) assay was conducted using the expression vector pSVOA5' containing the 379-bp c-fos promoter with and without a mutation in cAMP response element (CRE).

RESULTS. PGD₂ treatment induced c-fos mRNA, stimulated pericyte growth, and increased expression of VEGF mRNA. PGE₂ and -F₂ had similar effects on c-fos induction and pericyte growth, whereas PGI₂ was ineffective. RT-PCR confirmed that mRNAs corresponding to the receptors for PGD₂, -E₂, -F₂, and -I₂ were expressed in human retinal pericytes. Stimulation by PGD₂ led to phosphorylation of CREB, but had negligible effect on phosphorylation of p44/42 MAPK. The adenylyl cyclase inhibitor inhibited CREB activation and c-fos induction by PGD₂. In a reporter gene assay, c-fos induction occurred only with wild-type c-fos promoter. Mutation in CRE eliminated the response to PGD₂.

CONCLUSIONS. PGD₂ promotes the growth of retinal capillary pericytes by signaling through cAMP and CREB. The findings underscore the importance of PGs in the growth of human retinal capillary pericytes and raise the possibility that PGs may play a role in proliferative retinopathies.

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