Expression of Vascular Endothelial Growth/Permeability Factor by Endometrial Glandular Epithelial and Stromal Cells in Baboons during the Menstrual Cycle and after Ovariectomy

Abstract

Vascular endothelial growth/permeability factor (VEG/PF) has a crucial role in angiogenesis, and neovascularization is essential in preparing the uterine endometrium for implantation. However, the regulation of VEG/PF synthesis by particular cell types of the endometrium during the human menstrual cycle is not well understood. Therefore, in the present study the baboon was used as a nonhuman primate to determine the role of the ovary in vivo in endometrial VEG/PF expression. VEG/PF mRNA levels were quantified by competitive RT-PCR in whole uterine endometrium and in glandular epithelial and stromal cells isolated from the endometrium by laser capture microdissection of baboons during the normal menstrual cycle and after ovariectomy, which decreased serum estradiol and progesterone to undetectable levels. Mean (+/-SE) levels (attomoles per micrograms of total RNA) of the 323-bp VEG/PF mRNA product, which reflected collective expression of all VEG/PF isoforms, in whole endometrium were 785 and 727 +/- 158 during the mid and late follicular phases, respectively, and 1108 +/- 320 during the midcycle surge in serum estradiol. VEG/PF mRNA levels then declined briefly before increasing to 1029 +/- 365 attomoles/ micro g RNA during the late luteal phase of the menstrual cycle. VEG/PF mRNA levels (attomoles per femtomole of 18S rRNA) were similar in glandular epithelial (2.27 +/- 1.11) and stromal (2.54 +/- 0.70) cells at the midcycle estradiol peak and the midluteal phase of the menstrual cycle (2.34 +/- 1.30 and 1.49 +/- 0.53, respectively). Immunocytochemical expression of VEG/PF protein was abundant in glandular and luminal epithelium, stroma, and vascular endothelium. Endometrial vessel density and percent vascularized area, determined by morphometric image analysis, were similar during the various stages of the baboon menstrual cycle. After ovariectomy, VEG/PF mRNA levels (attomoles per femtomole of 18S rRNA) in the endometrial glands (0.52 +/- 0.21) and stroma (0.22 +/- 0.11) were decreased to values that were approximately 20% and 10% (P < 0.05), respectively, of those in intact baboons during the midcycle estrogen surge. Moreover, there was relatively little VEG/PF protein immunostaining in the endometrial glands, stroma, and vascular endothelium after ovariectomy. In summary, VEG/PF mRNA and protein expression in glandular epithelial and stromal cells were markedly suppressed after ovariectomy, indicating that synthesis of this angiogenic factor in these endometrial cells is dependent upon a product(s) secreted by the ovary. Moreover, endometrial VEG/PF expression remained relatively constant and thus was available as a component of the angiogenic system throughout the menstrual cycle, presumably to progressively promote vascular reconstruction of the endometrium.

Vascular Endothelial Growth Factor Genotypes, Haplotypes, Gender, and the Risk of Non–Small Cell Lung Cancer

“…Both in vitro and in vivo studies have proved that androgen could up-regulate VEGF expression (34,35), whereas androgen ablation inhibited VEGF expression (36). On the contrary, estrogen reduced VEGF expression (37,38).…”

Regulation of endometrial vascular remodelling: role of the vascular endothelial growth factor family and the angiopoietin–TIE signalling system

“…Various studies have now shown that the different VEGFA isoforms are present in the endometrium (Charnock-Jones et al 1993, Halder et al 2000, Sharkey et al 2000, Ancelin et al 2002, Niklaus et al 2002, Sugino et al 2002. As in other tissues, VEGFA 164 is believed to be the dominant isoform in human endometrium.…”

Cytokines: Important for implantation?

“…In some species, VEGF is expressed in placentomes [153]. VEGF is partly regulated by hormones during the cycle as well as chorionic gonadotropin at implantation and [146,147,[153][154][155][156][157]. Indeed mefipristone down-regulates local VEGF production [158], whereas, conversely, HLA-G (a non polymorphic Class I HLA antigen present on extravillous human trophoblasts), while inhibiting NK cell mediated cytotoxicity [2,122,[159][160][161], up-regulates VEGF production by uNK cells [162], a property fitting with a role of HLA-G in angiogenesis [163].…”