Luteal angiogenesis: Prevention and intervention by treatment with vascular endothelial growth factor Trap(A40)

The possibility of stimulating or inhibiting paracrine factors regulating a ngiogenesis may lead to new approaches for the treatment of pathological co nditions of the female reproductive tract. We examined the effects of a cli nical candidate, a soluble truncated form of the Flt-1 receptor, vascular e ndothelial growth factor trap(A40) (VEGF trap), in a primate model to deter mine its ability to prevent the onset of luteal angiogenesis or intervene w ith 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 (inter vention regimen). Effects of VEGF inhibition were studied by obtaining a pr oliferation index using bromodeoxyuridine incorporation, quantifying endoth elial cell area using CD31, and assessing luteal function by plasma progest erone. After both treatments, intense luteal endothelial proliferation was suppressed, a concomitant decrease in endothelial cell area confirmed the i nhibition 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 o f angiogenic genes. VEGF messenger ribonucleic acid (mRNA) expression in lu teal cells was increased, whereas expression of its receptor, Fit, was decr eased. inhibition of VEGF resulted in localized increased expression of ang iopoietin-2 mRNA and its receptor, Tie-2. The results show that the VEGF trap can prevent luteal angiogenesis and inh ibit the established process with resultant suppression of luteal function. Luteal Fit mRNA expression is dependent upon VEGF, and VEGF inhibition res ults in abortive increases in expression of VEGF, angiopoietin-2, and Tie-2 .