Angiogenesis in the Corpus Luteum of Early Pregnancy in the Marmoset and the Effects of Vascular Endothelial Growth Factor Immunoneutralization on Establishment of Pregnancy

Abstract

This study investigated vascular and molecular changes in the corpus luteum (CL) of early pregnancy in the marmoset. Ovaries were studied on Days 21 (n = 6) and 28 (n = 6) of pregnancy and compared with corpora lutea from Day 21 (late luteal) of the nonconception cycle (n = 8). Endothelial cell proliferation was measured by immunocytochemical detection of incorporated bromodeoxyuridine. Endothelial cell and pericyte area were assessed by quantitative immunocytochemistry for CD31 and alpha-smooth muscle actin, respectively. Vascular endothelial growth factor (VEGF) and its receptors, kinase insert domain-containing region (KDR) and fms-like tyrosine kinase (Flt) mRNA, were localized and quantified in in situ hybridization. In addition, the effects of immunoneutralization of VEGF on establishment and maintenance of pregnancy were investigated by administering a VEGF neutralizing antibody on Days 0-10 of the luteal phase during potentially fertile cycles (n = 10) and compared with fertile controls (n = 6). No differences in the cellular or morphological parameters were found between pregnant and structurally intact nonpregnant corpora lutea. No major differences were found in expression of VEGF, Flt, or KDR in these CL. VEGF immunoneutralization markedly suppressed plasma progesterone secretion during treatment, but pregnancy rate was not significantly reduced. Thus, a role for VEGF in early pregnancy in the marmoset remains to be established. These results show that, by the late luteal phase in the marmoset, the corpus luteum has established a mature vascular system and the molecular capacity to synthesize VEGF and its receptors. A pregnancy-induced spurt of angiogenesis or gene expression does not appear to take place; rather, maintenance of the existing vasculature is all that is required for the establishment of pregnancy.

Immunoneutralization of vascular endothelial growth factor inhibits pregnancy establishment in the rhesus monkey (Macaca mulatta)

“…The observation of the present study corroborates well with our earlier pilot study (Ghosh & Sengupta 2005). Contrary to our observations, Rowe et al (2002) observed that anti-VEGF Mab administration via i.v. route on days 0-10 of luteal phase to marmosets did not affect the pregnancy rate, although plasma progesterone secretion was markedly suppressed compared with animals exposed to mouse g-globulin during the same period.…”

Vascular Changes in the Corpus Luteum During Early Pregnancy in the Cow

“…In the present study, there was no change in VEGF120 and VEGF164 mRNA expression between the late luteal phase and early pregnancy. These findings correspond to the non-elevated VEGF expression in the marmoset [30] and bovine CL [29] during early pregnancy. In early human pregnancy, VEGF expression is remarkably high compared with that in the mid-luteal phase [12].…”

Microvascular Endothelial Cells of the Bovine Corpus Luteum: A Comparative Examination of the Estrous Cycle and Pregnancy

“…There is general agreement that a surge of angiogenesis occurs within the CL during its initial development, which is characterized by increased proliferation of endothelial cells and secretion of vascular endothelial cell growth factor (VEGF), and the upregulation of angiopoetins [9][10][11][12][13][14][15]. There is discrepancy, however, about whether or not a second surge of angiogenesis occurs during early pregnancy [9,11,13,16]. Collectively, these observations have led us to consider whether microvascular endot- helial cells might differ physically and functionally between CL of the estrous cycle and pregnancy.…”