Luteal angiogenesis: prevention and intervention by treatment with vascular endothelial growth factor trap(A40).
The possibility of stimulating or inhibiting paracrine factors regulating angiogenesis may lead to new approaches for the treatment of pathological conditions of the female reproductive tract. We examined the effects of a clinical candidate, a soluble truncated form of the Flt-1 receptor, vascular endothelial growth factor trap(A40) (VEGF trap), in a primate model to determine its ability to prevent the onset of luteal angiogenesis or intervene with the on-going process. Marmosets were treated from the day of ovulation until luteal day 3 (prevention regimen) or on luteal day 3 for 1 day (intervention regimen). Effects of VEGF inhibition were studied by obtaining a proliferation index using bromodeoxyuridine incorporation, quantifying endothelial cell area using CD31, and assessing luteal function by plasma progesterone. After both treatments, intense luteal endothelial proliferation was suppressed, a concomitant decrease in endothelial cell area confirmed the inhibition of vascular development, and a marked fall in plasma progesterone levels showed that luteal function was compromised. In situ hybridization was used to localize and quantify compensatory effects on the expression of angiogenic genes. VEGF messenger ribonucleic acid (mRNA) expression in luteal cells was increased, whereas expression of its receptor, Flt, was decreased. Inhibition of VEGF resulted in localized increased expression of angiopoietin-2 mRNA and its receptor, Tie-2. The results show that the VEGF trap can prevent luteal angiogenesis and inhibit the established process with resultant suppression of luteal function. Luteal Flt mRNA expression is dependent upon VEGF, and VEGF inhibition results in abortive increases in expression of VEGF, angiopoietin-2, and Tie-2.
Wulff
C
C
Medical Research Council Human Reproductive Sciences Unit, Edinburgh, Scotland, United Kingdom EH3 9ET. c.wulff@hrsu.mrc.ac.uk
Wilson
H
H
Rudge
J S
JS
Wiegand
S J
SJ
Lunn
S F
SF
Fraser
H M
HM
D042702:Angiopoietin-2; D000818:Animals; D001973:Bromodeoxyuridine / Q000032:analysis / Q000378:metabolism; D002144:Callithrix; D002455:Cell Division; D003338:Corpus Luteum / Q000098:blood supply* / Q000502:physiology; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D005260:Female; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D017403:In Situ Hybridization; D008183:Luteal Phase / Q000187:drug effects; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009929:Organ Size; D010053:Ovary / Q000033:anatomy & histology; D010060:Ovulation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011374:Progesterone / Q000097:blood; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D017978:Receptors, Growth Factor / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D042702:Angiopoietin-2; D016228:Endothelial Growth Factors; D007141:Immunoglobulin Fc Fragments; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011374:Progesterone; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D001973:Bromodeoxyuridine