title: Single-chain bifunctional vascular endothelial growth factor (VEGF)-follicle-stimulating hormone (FSH)-C-terminal peptide (CTP) is superior to the combination therapy of recombinant VEGF plus FSH-CTP in stimulating angiogenesis during ovarian folliculogenesis.
abstract: Infertility technologies often employ exogenous gonadotropin therapy to increase antral follicle production. In an effort to enhance ovarian response, several long-acting FSH therapies have been developed including an FSH-C-terminal peptide (CTP), where the FSH subunits are linked by the CTP moiety from human chorionic gonadotropin, which is responsible for the increased half-life of human chorionic gonadotropin. We found that administration of FSH-CTP for ovarian hyperstimulation in rats blunted ovarian follicle vascular development. In women, reduced ovarian vasculature has been associated with lower pregnancy rates. We were interested in determining whether vascular endothelial growth factor (VEGF) therapy could enhance ovarian angiogenesis in FSH-CTP-treated rats. Coadministration of systemic FSH-CTP plus recombinant VEGF was compared with treatment with a novel, single-chain bifunctional VEGF-FSH-CTP (VFC) analog. For VFC, the FSH portion targets the protein to the ovary and stimulates follicle growth, whereas VEGF enhances local vascular development. Both in vitro and in vivo studies confirm the dual FSH and VEGF action of the VFC protein. Evaluation of ovarian follicle development demonstrates that administration of combination therapy using VEGF and FSH-CTP failed to increase follicle vasculature above levels seen with FSH-CTP monotherapy. However, treatment with VFC significantly increased follicle vascular development while concurrently increasing the number of large antral follicles produced. In conclusion, we report the production and characterization of a long-acting, bifunctional VEGF-FSH-CTP protein that is superior to combination therapy for enhancing VEGF activity in the ovary and stimulating follicular angiogenesis in rats.
authors.affiliation: Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York City, NY 10032, USA.
authors.forename: Rhonda K
authors.initials: RK
authors.lastname: Trousdale
authors.forename: Susan V
authors.initials: SV
authors.lastname: Pollak
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Klein
authors.forename: Leslie
authors.initials: L
authors.lastname: Lobel
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Funahashi
authors.forename: Nikki
authors.initials: N
authors.lastname: Feirt
authors.forename: Joyce W
authors.initials: JW
authors.lastname: Lustbader
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D005260:Female; D005300:Fertility Agents, Female / Q000627:therapeutic use; D005640:Follicle Stimulating Hormone / Q000737:chemistry / Q000627:therapeutic use*; D006207:Half-Life; D007247:Infertility, Female / Q000188:drug therapy / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D006080:Ovarian Follicle / Q000098:blood supply* / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D010446:Peptide Fragments / Q000627:therapeutic use; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D004338:Drug Combinations; D005300:Fertility Agents, Female; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D005640:Follicle Stimulating Hormone