title: VEGFR-3 neutralization inhibits ovarian lymphangiogenesis, follicle maturation, and murine pregnancy.
abstract: Lymphatic vessels surround follicles within the ovary, but their roles in folliculogenesis and pregnancy, as well as the necessity of lymphangiogenesis in follicle maturation and health, are undefined. We used systemic delivery of mF4-31C1, a specific antagonist vascular endothelial growth factor receptor 3 (VEGFR-3) antibody to block lymphangiogenesis in mice. VEGFR-3 neutralization for 2 weeks before mating blocked ovarian lymphangiogenesis at all stages of follicle maturation, most notably around corpora lutea, without significantly affecting follicular blood angiogenesis. The numbers of oocytes ovulated, fertilized, and implanted in the uterus were normal in these mice; however, pregnancies were unsuccessful because of retarded fetal growth and miscarriage. Fewer patent secondary follicles were isolated from treated ovaries, and isolated blastocysts exhibited reduced cell densities. Embryos from VEGFR-3-neutralized dams developed normally when transferred to untreated surrogates. Conversely, normal embryos transferred into mF4-31C1-treated dams led to the same fetal deficiencies observed with in situ gestation. Although no significant changes were measured in uterine blood or lymphatic vascular densities, VEGFR-3 neutralization reduced serum and ovarian estradiol concentrations during gestation. VEGFR-3-mediated lymphangiogenesis thus appears to modulate the folliculogenic microenvironment and may be necessary for maintenance of hormone levels during pregnancy; both of these are novel roles for the lymphatic vasculature.
authors.affiliation: Institute of Bioengineering, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Rutkowski
authors.affiliation: Institute of Bioengineering, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Ihm
authors.affiliation: Institute of Bioengineering, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Seung Tae
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Institute of Bioengineering, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Witold W
authors.initials: WW
authors.lastname: Kilarski
authors.affiliation: Institute of Bioengineering, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Veronique I
authors.initials: VI
authors.lastname: Greenwood
authors.affiliation: Institute of Bioengineering, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Miriella C
authors.initials: MC
authors.lastname: Pasquier
authors.affiliation: Global Health Institute, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Quazzola
authors.affiliation: Global Health Institute, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
authors.affiliation: Institute of Bioengineering, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
authors.affiliation: Institute of Bioengineering, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Electronic address: melody.swartz@epfl.ch.
authors.forename: Melody A
authors.initials: MA
authors.lastname: Swartz
mesh_terms: D000022:Abortion, Spontaneous / Q000378:metabolism / Q000473:pathology; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D005306:Fertilization / Q000187:drug effects; D047109:Fetal Development / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D042583:Lymphangiogenesis / Q000187:drug effects; D042601:Lymphatic Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009500:Neutralization Tests; D006080:Ovarian Follicle / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D011247:Pregnancy; D011256:Pregnancy Outcome; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D057134:Antibodies, Neutralizing; D040321:Vascular Endothelial Growth Factor Receptor-3
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