The vascular endothelial growth factor (VEGF)/VEGF receptor 2 pathway is critical for blood vessel survival in corpora lutea of pregnancy in the rodent.
The vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR-2) pathway regulates proliferation, survival, and permeability of vasculature. This pathway is active during the formation of a corpus luteum, a highly vascularized, endocrine organ with a short life span during the nonpregnant state. In the pregnant state, the life span of corpora lutea is much longer because they play a critical role in supporting pregnancy development. We hypothesized that the VEGF/VEGFR-2 pathway plays a critical role in regulating angiogenic events in the corpora lutea of pregnancy. Injection of the neutralizing anti-VEGFR-2 antibody DC101 (ImClone Systems, Inc., New York, NY) on embryonic d 3.5 (preimplantation) or 6.5 (postimplantation) disrupts function of the corpora lutea of pregnancy in CD1 mice, as evidenced by a decrease in organ size, regression of luteal vessels, and a fall in progesterone secretion within 24 h postinjection. Inhibition of the VEGFR-2 caused removal of endothelial cells, mostly through endothelial cell detachment from the vascular basement membrane. Luteal steroid-producing epithelial cells were eliminated through apoptosis secondary to vasculature becoming dysfunctional. Disruption of luteal function caused arrest of embryonic development. The effect of antibody is specific to the ovary, because pregnancy progresses normally in ovariectomized, progesterone-replaced animals treated with anti-VEGFR-2 antibody. Embryonic blood vessels were not affected directly by the antibody, because it did not reach the embryo. Administration of an antibody against VE-cadherin (E4G10), which specifically blocks endothelial proliferation, did not disrupt luteal function and pregnancy development. Thus, VEGFR-2-mediated endothelial cell signals are critical to maintain functionality of luteal blood vessels during pregnancy. Potential clinical applications of inhibitors of the VEGF/VEGFR-2 pathway include emergency contraception and medical treatment of ectopic and abnormal intrauterine pregnancies.
Pauli
Samuel A
SA
Department of Obstetrics and Gynecology, Yale University, New Haven, Connecticut 06520, USA.
Tang
Hongyan
H
Wang
Jeff
J
Bohlen
Peter
P
Posser
Robert
R
Hartman
Tipton
T
Sauer
Mark V
MV
Kitajewski
Jan
J
Zimmermann
Ralf C
RC
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD; D017209:Apoptosis; D001485:Basement Membrane / Q000378:metabolism; D001755:Blastocyst; D001808:Blood Vessels / Q000378:metabolism*; D015820:Cadherins / Q000737:chemistry; D049109:Cell Proliferation; D003338:Corpus Luteum / Q000502:physiology*; D047108:Embryonic Development; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D008856:Microscopy, Fluorescence; D010053:Ovary / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D013997:Time Factors; D014599:Uterus / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D000099152:Cadherin 5
D000906:Antibodies; D015703:Antigens, CD; D015820:Cadherins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5