Luteal Angiogenesis: Prevention and Intervention by Treatment with Vascular Endothelial Growth Factor TrapA40

Abstract

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.

Short oestrous cycles in sheep during anoestrus involve defects in progesterone biosynthesis and luteal neovascularisation

“…Inhibition of LH signalling using GNRH antagonists mimicked this effect, also suppressing early luteal angiogenesis and implicating the LH surge in normal luteal angiogenesis, consistent with the described induction of VEGFA signalling by LH (Koos 1995, Dickson & Fraser 2000. The in vivo inhibition of VEGFA signalling throughout the luteal phase (days 3-10 in the marmoset monkey) also decreased luteal angiogenesis and the blood concentration of progesterone (Dickson et al 2001, Wulff et al 2001c. Recently, a study carried out by Christensen et al (2012) indicated that treatment with progesterone increased the levels of VEGFA, KDR and angiopoietin 1 (ANGPT1 (ANG1)) in the CL of anoestrous ewes.…”

“…Modulation of angiogenesis during the luteal phase by Luteal failure and the short cycle in ewes treatment with inhibitors of VEGFA signalling either at or shortly following ovulation significantly reduced the number of proliferative and endothelial cells within the CL and significantly decreased progesterone secretion (Wulff et al 2001c, Hazzard et al 2002, while a more prolonged treatment, well into the luteal phase, resulted in a complete ablation of microvascular branching (Wulff et al 2001a(Wulff et al , 2001b. Inhibition of LH signalling using GNRH antagonists mimicked this effect, also suppressing early luteal angiogenesis and implicating the LH surge in normal luteal angiogenesis, consistent with the described induction of VEGFA signalling by LH (Koos 1995, Dickson & Fraser 2000.…”

Expression and significance of angiopoietin-2 in gastric cancer

“…Angiopoietins were mainly produced by endothelial cells and pericytes, and their receptor Tie-2 was also expressed in endothelial cells and pertly in hematopoietic cells [23] . Ang-2 was selectively expressed in endothelial cells of tumors, ovaries, uterus and placenta, which are known to have extensive vascularization patterns [24][25][26] . The role and mechanism of Ang-2 in tumor angiogenesis have not been clarified.…”

The effects of ergot and non-ergot-derived dopamine agonists in an experimental mouse model of endometriosis

“…However, the commercial anti-VEGF/VEGFR2 used in such experiments can induce severe side effects (Eremina et al 2008), which rules out its use in the treatment of endometriosis in young and otherwise healthy women. Moreover, such compounds can also affect other important physiologic processes, including early pregnancy, by blocking implantation-related ovarian (Wulff et al 2001, Zimmermann et al 2001a, 2001b, Pauli et al 2005 and uterine angiogenesis (Rockwell et al 2002, Heryanto et al 2003.…”