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Presence and Regulation of Endocrine Gland Vascular Endothelial Growth Factor/Prokineticin-1 and Its Receptors in Ovarian Cells

Department of Animal Sciences, The Hebrew University of Jerusalem (T.K., N.L., R.M.), Rehovot 76100, Israel; and Department of Obstetrics and Gynecology, Hadassah University Hospital (A.H.), Jerusalem 91905, Israel

Address correspondence and requests for reprints to: Rina Meidan, Department of Animal Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel. E-mail: rina.meidan{at}huji.ac.il.

Endocrine gland vascular endothelial growth factor (EG-VEGF) is a novel angiogenic mitogen selective for endothelial cells (EC) in endocrine glands. EG-VEGF is identical to a protein previously cloned and termed prokineticin (PK)-1. The present study examined the expression of EG-VEGF/PK-1 and its receptors in ovarian steroidogenic cells and EC and compared the regulation of EG-VEGF/PK-1 and VEGF expression in SV40 transformed luteinized human granulosa cell line (SVOG). Normal granulosa or SVOG cells expressed EG-VEGF/PK-1 mRNA. Incubation of SVOG cells with forskolin augmented EG-VEGF/PK-1 expression in a dose-dependent manner. Chemical hypoxia induced by CoCl₂ and desferrioxamine mesylate (100 µM each) markedly reduced EG-VEGF/PK-1. In contrast, hypoxia significantly elevated VEGF mRNA (VEGF165, 189) and protein secretion. Thrombin, like hypoxia, also induced an opposite effect on VEGF and EG-VEGF/PK-1. Whereas EG-VEGF/PK-1 and VEGF were inversely regulated, steroidogenesis and EG-VEGF/PK-1 were positively correlated in SVOG cells. A distinct pattern of ovarian PK receptor (PK-R) expression was observed in which steroidogenic cells predominantly express PK-R1 receptors, whereas corpus luteum-derived EC express high levels of both PK-R1 and PK-R2. Therefore, acting via either PK-R2 or PK-R1, EG-VEGF/PK-1 may have angiogenic as well as nonangiogenic functions in the ovary.

This study was supported by a grant from the The United States–Israel Binational Agricultural Research and Development Fund.

Abbreviations: BAEC, Bovine aortic EC; BS-1, Bandeiraea simplicifolia lectin-1; CL, corpus luteum; DFX, deferoxamine mesylate; EC, endothelial cells; EG-VEGF, endocrine gland-VEGF; FCS, fetal calf serum; G3PDH, glyceraldehyde 3-phosphate dehydrogenase; GI, gastrointestinal; hGC, human granulosa cell; HIF-1, hypoxia inducible factor 1; hLGC, human luteinized granulosa cells; HUVEC, human umbilical vein EC; P450scc, P450 side-chain cleavage enzyme; PK, prokineticin; PK-R, PK receptor; StAR, steroidogenic acute regulatory protein; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

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