scholarly journals The role of progesterone in endometrial angiogenesis in pregnant and ovariectomised mice

Reproduction ◽  
2005 ◽  
Vol 129 (6) ◽  
pp. 765-777 ◽  
Author(s):  
Lisa M Walter ◽  
Peter A W Rogers ◽  
Jane E Girling
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Plasma Progesterone ◽  
Ovariectomized Mice ◽  
Pregnant Mice ◽  
Endothelial Growth Factor

The role of progesterone (and oestrogen) in endometrial angiogenesis remains controversial. The aims of this study were to quantify endometrial angiogenesis in pregnant mice and to investigate the role of progesterone in promoting endothelial cell proliferation in ovariectomized mice. Uteri were collected on days 1 to 4 of pregnancy when circulating progesterone concentrations were increasing, prior to implantation. Before dissection, mice were injected with bromodeoxyuridine (BrdU) enabling proliferating endothelial cells to be quantified with CD31/BrdU double-immunohistochemistry. There was a significant increase in proliferating endothelial cells on day 3 of pregnancy when plasma progesterone also increased. To determine if this endothelial cell proliferation was due to progesterone, an experiment was performed on ovariectomised mice. One group was treated with a single oestradiol injection on day 8 after ovariectomy, followed by a no-treatment day and three consecutive daily injections of progesterone. Other groups were treated with either the vehicle, oestradiol or progesterone injections only; all were dissected on day 13 following ovariectomy. Unexpectedly, mice treated with progesterone-only had the highest amount of endothelial cell proliferation and oestrogen priming was found to significantly reduce this progesterone-induced endothelial cell proliferation. To determine if this proliferation is mediated by vascular endothelial growth factor (VEGF), a further experiment in which VEGF anti-serum was administered concurrently with the progesterone injections was performed. Endothelial cell proliferation was reduced but not abolished suggesting progesterone-induced endometrial angiogenesis is only partly mediated by VEGF. Results indicate that oestrogen priming is not required for progesterone to stimulate endometrial endothelial cell proliferation and that oestrogen inhibits progesterone-induced angiogenesis in ovariectomised mice.

scholarly journals Intravascular neutrophils partially mediate the endometrial endothelial cell proliferative response to oestrogen in ovariectomised mice

Reproduction ◽  
2004 ◽  
Vol 127 (5) ◽  
pp. 613-620 ◽  
Author(s):  
B Heryanto ◽  
J E Girling ◽  
P A W Rogers
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cell ◽  
Proliferative Response ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Proliferating Cells ◽  
Oestrogen Treatment ◽  
Neutrophil Depletion ◽  
Endothelial Growth Factor

The aim of this study was to investigate the role of intravascular neutrophils in initiating endothelial cell proliferation following oestrogen treatment in ovariectomised mouse endometrium. Uterine tissues were collected from ovariectomised C57/CBA female mice 24 h after oestrogen treatment with or without systemic neutrophil depletion. Neutropenia was achieved with either an in-house anti-neutrophil serum (ANS) or Gr-1 monoclonal antibody. All mice received an i.p. injection of bromodeoxyuridine (BrdU) 4 h prior to dissection to allow visualisation of proliferating cells using immunocytochemistry. Endometrial sections were immunostained for BrdU, vascular endothelial growth factor (VEGF), and neutrophils (using ANS). Oestrogen treatment of ovariectomised mice significantly increased the number of intravascular neutrophils, whereas induction of neutropenia with either ANS or Gr-1 in conjunction with oestrogen treatment prevented this increase. Oestrogen treatment of ovariectomised mice also significantly increased the number of intravascular VEGF-positive cells; however, whereas induction of neutropenia with ANS significantly reduced this increase, Gr-1 did not. In both studies, neutropenia significantly reduced, but did not eliminate, the amount of endometrial endothelial cell proliferation. These results suggest a role for neutrophils in endometrial angiogenesis following acute oestrogen treatment; however, the presence of VEGF-positive cells even after induction of neutropenia suggests that more than one type of leukocyte may be involved.

scholarly journals Vascular Endothelial Growth Factor Mediates the Estrogen-Induced Breakdown of Tight Junctions between and Increase in Proliferation of Microvessel Endothelial Cells in the Baboon Endometrium

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6076-6083 ◽  
Author(s):  
Graham W. Aberdeen ◽  
Stanley J. Wiegand ◽  
Thomas W. Bonagura ◽  
Gerald J. Pepe ◽  
Eugene D. Albrecht
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Tight Junctions ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
Vegf Trap

To assess whether there is a link between estrogen, vascular endothelial growth factor (VEGF), and early aspects of uterine angiogenesis, an acute temporal study was conducted in which ovariectomized baboons were pretreated with VEGF Trap, which sequesters endogenous VEGF, and administered estradiol at time 0 h. Serum estradiol levels approximated 500 pg/ml 4–6 h after estradiol administration. VEGF mRNA levels in endometrial glandular epithelial and stromal cells were increased to values 6 h after estradiol that were 3.74 ± 0.99-fold (mean ± se) and 5.70 ± 1.60-fold greater (P < 0.05), respectively, than at 0 h. Microvessel interendothelial cell tight junctions, which control paracellular permeability, were present in the endometrium at time 0 h, but not evident 6 h after estradiol administration. Thus, microvessel paracellular cleft width increased (P < 0.01, ANOVA) from 5.03 ± 0.22 nm at 0 h to 7.27 ± 0.48 nm 6 h after estrogen. In contrast, tight junctions remained intact, and paracellular cleft widths were unaltered in estradiol/VEGF Trap and vehicle-treated animals. Endometrial microvessel endothelial cell mitosis, i.e. percent Ki67+/Ki67− immunolabeled endothelial cells, increased (P < 0.05) from 2.9 ± 0.3% at 0 h to 21.4 ± 7.0% 6 h after estrogen treatment but was unchanged in estradiol/VEGF Trap and vehicle-treated animals. In summary, the estrogen-induced disruption of endometrial microvessel endothelial tight junctions and increase in endothelial cell proliferation were prevented by VEGF Trap. Therefore, we propose that VEGF mediates the estrogen-induced increase in microvessel permeability and endothelial cell proliferation as early steps in angiogenesis in the primate endometrium.

scholarly journals Mid-luteal angiogenesis and function in the primate is dependent on vascular endothelial growth factor

2001 ◽  
Vol 168 (3) ◽  
pp. 409-416 ◽  
Author(s):  
SE Dickson ◽  
R Bicknell ◽  
HM Fraser
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Luteal Phase ◽  
Smooth Muscle Actin ◽  
Proliferation Index ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is essential for the angiogenesis required for the formation of the corpus luteum; however, its role in ongoing luteal angiogenesis and in the maintenance of the established vascular network is unknown. The aim of this study was to determine whether VEGF inhibition could intervene in ongoing luteal angiogenesis using immunoneutralisation of VEGF starting in the mid-luteal phase. In addition, the effects on endothelial cell survival and the recruitment of periendothelial support cells were examined. Treatment with a monoclonal antibody to VEGF, or mouse gamma globulin for control animals, commenced on day 7 after ovulation and continued for 3 days. Bromodeoxyuridine (BrdU), used to label proliferating cells to obtain a proliferation index, was administered one hour before collecting ovaries from control and treated animals. Ovarian sections were stained using antibodies to BrdU, the endothelial cell marker, CD31, the pericyte marker, alpha-smooth muscle actin, and 3' end DNA fragments as a marker for apoptosis. VEGF immunoneutralisation significantly suppressed endothelial cell proliferation and the area occupied by endothelial cells while increasing pericyte coverage and the incidence of endothelial cell apoptosis. Luteal function was markedly compromised by anti-VEGF treatment as judged by a 50% reduction in plasma progesterone concentration. It is concluded that ongoing angiogenesis in the mid-luteal phase is primarily driven by VEGF, and that a proportion of endothelial cells of the mid-luteal phase vasculature are dependent on VEGF support.

Evidence for telomerase involvement in the angiogenesis of astrocytic tumors: expression of human telomerase reverse transcriptase messenger RNA by vascular endothelial cells

2001 ◽  
Vol 94 (6) ◽  
pp. 961-971 ◽  
Author(s):  
Roberto Pallini ◽  
Francesco Pierconti ◽  
Maria Laura Falchetti ◽  
Daniela D'Arcangelo ◽  
Eduardo Fernandez ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Astrocytic Tumors ◽  
Htert Mrna ◽  
Content Type ◽  
Human Telomerase ◽  
Fine Print

Object. Evidence from recent in vitro studies indicates that reactivation of telomerase, the enzyme that synthesizes the telomere ends of chromosomes, is a crucial event in the unlimited clonal expansion of endothelial cells that precedes the neoplastic conversion of these cells. It is known that high-grade gliomas express telomerase and that, in these neoplasms, proliferating endothelial cells may undergo transformational changes with development of sarcomatous components within the primitive tumor. To assess whether telomerase is involved in the endothelial cell proliferation that characterizes brain tumor angiogenesis, the authors investigated at the single-cell level the expression of messenger (m)RNA for the human telomerase catalytic subunit human telomerase reverse transcriptase (hTERT) by vascular cells of astrocytic tumors. Methods. The in situ hybridization (ISH) method was performed by processing histological sections with specific riboprobes for hTERT and for c-myc, an oncogene that is known to upregulate hTERT. Results of the ISH studies were compared with proliferative activity, as estimated by Ki-67 immunostaining. The expression of hTERT mRNA by vascular endothelial cells was related to the histological grade of the tumor because it was detected in five (29%) of 17 low-grade astrocytomas, nine (56%) of 16 anaplastic astrocytomas, and 19 (100%) of 19 glioblastomas multiforme (GBMs). Expression of c-myc mRNA was strictly correlated with that of hTERT mRNA. In low-grade astrocytomas and anaplastic astrocytomas, a dissociation was noted between hTERT mRNA expression and the proliferation rate of endothelial cells. Conversely, GBMs displayed a significant correlation between the level of hTERT mRNA expression and endothelial cell proliferation. Data from an in vitro assay in which human umbilical vein endothelial cells were stimulated to proliferate by adding vascular endothelial growth factor and an ISH study of newly formed vessels surrounding brain infarcts confirmed that expression of hTERT mRNA does not merely reflect the proliferative status of endothelial cells but represents a specific feature of brain tumor neovascularization. Conclusions. The results of this study are consistent with a role of telomerase in the angiogenesis of astrocytic tumors. Expression of hTERT mRNA by tumor vascular cells is an early event during the progression of astrocytic tumors, which precedes endothelial cell proliferation and may represent a first sign of dedifferentiation. Other than elucidating the mechanisms of tumor angiogenesis, these results encourage research on antitelomerase drugs for the treatment of malignant gliomas.

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