N of reproductive age. PCOS was initially described as a disorder characterized by the association of hirsutism, obesity, lowered fertility, and enlarged polycystic ovaries.6 Hyperplasia with the theca interna and stroma, with excessive production of androgens, are hallmarks of PCOS.7. Certainly, the ultrasonographic assessment of stromal area8 and blood flow9 is at present utilised as diagnostic test. Although PCOS was described much more than 50 years ago, its etiology has remained mainly unclear. Having said that, elevated luteinizing hormone/follicle-stimulating hormone ratio, defective collection of a dominant follicle, and anovulation are deemed to become essential elements with the pathogenesis. Current proof also indicates that PCOS is usually a component of a complex endocrine/metabolic disorder in which ADAM Metallopeptidase Domain 7 Proteins custom synthesis insulin resistance plays a major function.10 Prior research have shown that the vascular endothelial development factor (VEGF) mRNA expression is temporally and spatially related towards the proliferation of blood vessels inside the typical rat, mouse, and primate ovary, suggesting that VEGF may be a mediator in the cyclical growth of blood vessels that occurs within the female reproductive tract.11,12 Administration of VEGF inhibitors suppresses luteal angiogenesis135 and delays follicular deAccepted for publication February 28, 2003. Address reprint requests to Napoleone Ferrara, M.D. (E-mail: [email protected]) or Franklin Peale, M.D. (E-mail: [email protected]), Genentech Inc., 1 DNA Way, South San Francisco, CA 94080.1882 Ferrara et al AJP June 2003, Vol. 162, No.velopment16 in rodents and primates. In addition, several studies have implicated VEGF also in the angiogenesis associated with PCOS.17 Extra recently, an endothelial cell mitogen with an even higher degree of specificity than VEGF has been identified. This molecule, termed endocrine gland-derived (EG)VEGF, is expressed inside the human and primate ovary.18 Intriguingly, adenovirus-mediated delivery of EG-VEGF induced a powerful angiogenic response, accompanied by comprehensive cyst formation within the ovary, whereas it fails to possess important effects when delivered in other organs such as the skeletal muscle.18 Related to VEGF, the expression of EG-VEGF mRNA is Carboxypeptidase D Proteins Biological Activity up-regulated by hypoxia by a HIF-1 -dependent mechanism.19 EG-VEGF represents 1 of a structurally connected class of peptides ascribed a number of regulatory functions, including regulation of gastrointestinal motility and circadian rhythms.19 The first of those molecules, venom protein A, (VPRA),20 was purified from the venom of the black mamba snake as a nontoxic element. The other members of this family contain the digestive enzyme, colipase,21 the Xenopus head-organizer, dickkopf,22 and the secreted protein from the toad Bombina variegata, designated Bv8.23 EGVEGF, 80 homologous to VPRA, is probably the human orthologue of this molecule. EG-VEGF and VPRA are closely associated, 71 and 76 homologous, respectively, to the Bv8 peptide. Mouse and human orthologues of Bv8 (also referred to as prokineticin-2)24 have already been recently described. Inside the present study we have examined the expression of VEGF and EG-VEGF mRNA by in situ hybridization within a series of standard ovaries and PCOS specimens. The expression of KDR (VEGFR-2) mRNA and CD34 and CD31 proteins were used as markers of the endothelium of blood vessels. Benefits of these studies show that EGVEGF may possibly play a critical function, as well as VEGF, in each standard and pathological ovarian function.Components and MethodsSpecimens from 13 patients with.
