Preovulatory treatment of mice with anti-VEGF receptor 2 antibody inhibits angiogenesis in corpora lutea.
Adult mammalian angiogenesis occurs predominantly in female reproductive organs: the ovary and the uterus. Angiogenesis is very active during corpus luteum formation. A key regulator of angiogenesis is vascular endothelial growth factor (VEGF), which is highly expressed during corpus luteum formation. Inhibition of VEGF activity can block the formation and function of the corpora lutea by preventing angiogenesis. The VEGF receptor 2 (VEGF-R2) mediates the angiogenic action of VEGF and is expressed during corpus luteum formation. We hypothesized that treatment with an antibody against VEGF-R2 would inhibit luteal angiogenesis by blocking VEGF/VEGF-R2 interaction. Immature mice were induced to superovulate with PMSG/hCG resulting in neovascularization in the corpora lutea, as evidenced by abundant staining for the endothelial-specific adhesion molecule PECAM. Multiple doses of a monoclonal antibody against the VEGF-R2 (DC101) were administered to immature mice. Treatment was initiated 2 days prior to the induction of superovulation with PMSG/hCG. This antibody inhibited luteal angiogenesis as evidenced by the lack of PECAM staining in the center of the corpora lutea. Multiple dose treatment with antibody initiated prior to gonadotropin administration could not dissociate the luteal inhibition from the consequences of inhibition of angiogenesis in the developing follicle. Administration of a single, preovulatory dose of anti-VEGF-R2 antibody, such that follicular angiogenesis would not be affected, also inhibited luteal development, demonstrating that luteal angiogenesis is required for corpus luteal development. We conclude that VEGF acting through VEGF-R2 has an obligatory role in luteal angiogenesis and corpus luteum formation.
Zimmermann
R C
RC
Department of Ob/Gyn, Division of Reproductive Endocrinology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. rcz3@columbia.edu
Hartman
T
T
Bohlen
P
P
Sauer
M V
MV
Kitajewski
J
J
D000375:Aging; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D003338:Corpus Luteum / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D007668:Kidney / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic; D010053:Ovary / Q000502:physiology; D010060:Ovulation / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011374:Progesterone / Q000097:blood; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000276:immunology / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000906:Antibodies; D016228:Endothelial Growth Factors; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011374:Progesterone; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor