Inhibition of Vascular Endothelial Growth Factor/Vascular Permeability Factor Action Blocks Estrogen-Induced Uterine Edema and Implantation in Rodents1

This work examined how the conceptus modulates endometrial tissue remodeling and vascular development prior to implantation in mares. A macroscopic uterine examination was completed at day 21 of pregnancy. In situ morphology revealed that the endometrium involved in encroachment is restricted to the dorsal endometrium immediately overlying the yolk sac. The amount of stromal area occupied by blood vessels and the number of endometrial glands were increased during early pregnancy. Endometrial histomorphometry as well as the endometrial mRNA abundance and immunolocalization of VEGF, VEGFR1, VEGFR2, and Ki-67 was completed at days 14 and 21 of pregnancy, at day 10 of the estrous cycle, and during estrus. No obvious differences in VEGF and VEGFR1 protein localization were detected between pregnant and cycling mares but differential staining pattern for VEGFR2 and Ki-67 was observed. VEGFR2 localized to luminal and glandular epithelium of pregnant mares, while luminal epithelium was negative in cycling mares. Ki-67 staining was weak during the luteal phase but exhibited prominent luminal epithelium staining during estrus. In pregnant mares, all endometrial layers were Ki-67 positive. Quantitative RT-PCR revealed a greater abundance of VEGF mRNA during pregnancy. VEGFR2 transcript abundance was greatest in pregnant mares on day 21. This study supports the concept that the conceptus plays an active role in directing vasculogenesis within the uterus and thereby establishing hemotrophic nutrition that supports pregnancy after implantation.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Conceptus-mediated endometrial vascular changes during early pregnancy in mares: an anatomic, histomorphometric, and vascular endothelial growth factor receptor system immunolocalization and gene expression study

Silva¹,

Klein²,

Ealy³

et al. 2011

“…Uterine oedema decreased (lower echotexture scores) in the pregnant group after day 26, which may be a result of continued progesterone exposure. Mechanisms involved in the development of uterine oedema have been discussed (Rabbani & Rogers 2001, Rockwell et al 2002.…”

Section: Discussionmentioning

confidence: 99%

Local effect of the conceptus on uterine vascular perfusion during early pregnancy in heifers

Silva¹,

Ginther²

2010

Colour-Doppler ultrasonography was used to study the spatial relationship between vascular perfusion in the middle of each uterine horn and the reported location of the embryo proper and expanding conceptus using endometrial vascularity scores 1-4 (nil-maximal). Vascularity increased in both uterine horns between days 14 and 18 (day 0Zovulation) in nonpregnant heifers (nZ6) but not in pregnant heifers (nZ11). The increase was temporally associated with decreasing plasma progesterone and increasing oestradiol. In pregnant heifers, a transient increase in endometrial vascularity in the ipsilateral horn (horn with embryo) was not detected before day 18, despite a reported transient increase in blood flow in the ipsilateral uterine artery between days 13 and 17. Endometrial vascularity in the ipsilateral horn first increased (P!0.05) between days 18 and 20. Day 20 is the reported day of adhesiveness between chorion and uterus. An increase (P!0.05) in the contralateral horn between days 18 and 22 was slight, but a greater increase occurred after day 32. Day 32 is the reported day of entry of the allantochorion into the contralateral horn. By day 42, scores were similar between the two horns, and the allantochorion reportedly fills both horns. On days 42-60, at a time when placentomes apparently are limited to the ipsilateral horn, vascularity remained elevated in the ipsilateral horn but decreased in the contralateral horn. Results support the hypothesis that vascular perfusion in each uterine horn during early pregnancy is mediated by direct contact between conceptus and uterus.

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Delgado-Rosas¹,

Gómez²,

Ferrero³

et al. 2011

Implantation of a retrogradely shed endometrium during menstruation requires an adequate blood supply, which allows the growth of endometriotic lesions. This suggests that the development of endometriosis can be impaired by inhibiting angiogenesis. The growth of endometriotic foci is impaired by commercial oncological antiangiogenic drugs used to block vascular endothelial growth factor (VEGF) signaling. The dopamine agonist cabergoline (Cb2) inhibits the growth of established endometriosis lesions by exerting antiangiogenic effects through VEGFR2 inactivation. However, the use of ergot-derived Cb2 is associated with an increased incidence of cardiac valve regurgitation. To evaluate the potential usage of non-ergot-derived dopamine agonists for the treatment of human endometriosis, we compared the efficacy of quinagolide with that of Cb2 in preventing angiogenesis and vascularization in a heterologous mouse model of endometriosis. Nude mice whose peritoneum had been implanted with eutopic human endometrial fragments were treated with vehicle, 50 mg/kg per day oral Cb2, or 50 or 200 mg/kg per day quinagolide during a 14-day period. At the end of the treatment period, the implants were excised in order to assess lesion size, cell proliferation, degree of vascularization, and angiogenic gene expression. Neoangiogenesis was inhibited and the size of active endometriotic lesions, cellular proliferation index, and angiogenic gene expression were significantly reduced by both dopamine agonists when compared with the placebo. Given that Cb2 and quinagolide were equally effective in inhibiting angiogenesis and reducing lesion size, these experiments provide the rationale for pilot studies to explore the use of non-ergot-derived dopamine agonists for the treatment of endometriosis in humans.