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We investigated the mechanism underlying vascular endothelial growth factor (VEGF) synthesis stimulated by prostaglandin E1 (PGE1) in osteoblast-like MC3T3-E1 cells. PGE1 induced the phosphorylation of both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. SB203580, a specific inhibitor of p38 MAP kinase, inhibited the PGE1-stimulated VEGF synthesis as well as PGE1-induced phosphorylation of p38 MAP kinase. PD98059, an inhibitor of the upstream kinase that activates p44/p42 MAP kinase, which reduced the PGE1-induced phosphorylation of p44/p42 MAP kinase, had little effect on the VEGF synthesis stimulated by PGE1. AH-6809, an antagonist of the subtypes of the PGE receptor, EP1 and EP2, or SC-19220, an antagonist of EP1 receptor, did not inhibit the PGE1-induced VEGF synthesis. H-89, an inhibitor of cAMP-dependent protein kinase, and SQ22536, an inhibitor of adenylate cyclase, reduced the VEGF synthesis induced by PGE1. Cholera toxin, an activator of G(s), and forskolin, an activator of adenylate cyclase, induced VEGF synthesis. SB203580 and PD169316, another specific inhibitor of p38 MAP kinase, reduced the cholera toxin-, forskolin- or 8bromo-cAMP-stimulated VEGF synthesis. However, PD98059 failed to affect the VEGF synthesis stimulated by cholera toxin, forskolin or 8-bromoadenosine-3',5'-cyclic monophosphate (8bromo-cAMP). SB203580 reduced the phosphorylation of p38 MAP kinase induced by forskolin or 8bromo-cAMP. These results strongly suggest that p44/p42 MAP kinase activation is not involved in the PGE1-stimulated VEGF synthesis in osteoblasts but that p38 MAP kinase activation is involved.
Obstetrics and Gynecology, McGill University, 3655 Promenade Sir-William-Osler, Montréal, Québec, Canada H3G 1Y6
Toxicology Research Division, Health Products and Foods Branch, Food Directorate, Health Canada, Ottawa, Ontario, Canada
Reproductive Biology Unit, Departments of Cellular and Molecular Medicine and Obstetrics and Gynecology, University of Ottawa, Sir Frederick G Banting Research Centre, 2202D1 Tunney’s Pasture, Ottawa, Ontario, Canada K1A 0L2
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Obstetrics and Gynecology, McGill University, 3655 Promenade Sir-William-Osler, Montréal, Québec, Canada H3G 1Y6
Toxicology Research Division, Health Products and Foods Branch, Food Directorate, Health Canada, Ottawa, Ontario, Canada
Reproductive Biology Unit, Departments of Cellular and Molecular Medicine and Obstetrics and Gynecology, University of Ottawa, Sir Frederick G Banting Research Centre, 2202D1 Tunney’s Pasture, Ottawa, Ontario, Canada K1A 0L2
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Obstetrics and Gynecology, McGill University, 3655 Promenade Sir-William-Osler, Montréal, Québec, Canada H3G 1Y6
Toxicology Research Division, Health Products and Foods Branch, Food Directorate, Health Canada, Ottawa, Ontario, Canada
Reproductive Biology Unit, Departments of Cellular and Molecular Medicine and Obstetrics and Gynecology, University of Ottawa, Sir Frederick G Banting Research Centre, 2202D1 Tunney’s Pasture, Ottawa, Ontario, Canada K1A 0L2
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systems. Interestingly, there is recent evidence supporting a role for various growth factors in epididymal function; for example, the overexpression of VEGF in the testis and epididymis of transgenic mice results in infertility ( Korpelainen et al. 1998
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(ERK) activation leading to pro-proliferative and anti-apoptotic signaling ( Anneren & Welsh 2002 , Welsh et al . 2002 ). SHB also plays an important role in endothelial cells, where it associates with and relays signals from VEGF-activated VEGFR2
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We previously reported that basic fibroblast growth factor (FGF-2) activates p44/p42 mitogen-activated protein (MAP) kinase resulting in the stimulation of vascular endothelial growth factor (VEGF) release in osteoblast-like MC3T3-E1 cells and that FGF-2-activated p38 MAP kinase negatively regulates VEGF release. In the present study, we investigated the involvement of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in FGF-2-induced VEGF release in these cells. FGF-2 markedly induced the phosphorylation of SAPK/JNK. SP600125, an inhibitor of SAPK/JNK, markedly reduced the FGF-2-induced VEGF release. SP600125 suppressed the FGF-2-induced phosphorylation of SAPK/JNK without affecting the phosphorylation of p44/p42 MAP kinase or p38 MAP kinase induced by FGF-2. PD98059, an inhibitor of upstream kinase of p44/p42 MAP kinase, or SB203580, an inhibitor of p38 MAP kinase, failed to affect the FGF-2-induced phosphorylation of SAPK/JNK. A combination of SP600125 and SB203580 suppressed the FGF-2-stimulated VEGF release in an additive manner. These results strongly suggest that FGF-2 activates SAPK/JNK in osteoblasts, and that SAPK/JNK plays a part in FGF-2-induced VEGF release.
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Locally produced growth factors may have important modulatory roles in final ovarian follicular growth. The aim of this study was to investigate the possible participation of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2) in bovine follicles during final growth. Ovaries were collected from a slaughterhouse within 10-20 min after exsanguination. A classification of follicles into five groups (<0.5; >0.5-5; >5-20; >20-180; >180 ng/ml) was performed according to the follicular fluid (FF) oestradiol-17 beta content. For a better characterisation of classes the mRNA expressions of FSH receptor, LH receptor and aromatase cytochrome P450 in theca interna (TI) and granulosa cells (GC) were determined. Analysis of VEGF transcript by RT-PCR showed that GC and theca cells express predominantly the smallest isoforms (VEGF(121) and VEGF(165)). VEGF mRNA expression in both tissues (TI and GC) and VEGF protein concentration in total follicle tissue increased significantly (and correlated) with developmental stages of follicle growth. The expression of mRNA for VEGF receptor (VEGFR)-1 and VEGFR-2 was very weak in GC, without any regulatory change during final follicle growth. In contrast, TI showed strong expression of mRNA for both receptors in all follicle classes examined. VEGF protein concentrations in FF increased significantly and continuously to maximum levels in preovulatory follicles. As shown by immunohistochemistry, VEGF protein was clearly localised in TI and GC of preovulatory follicles. FGF2 and FGF receptor (FGFR) mRNA expression in TI increased significantly during final growth of follicles. In contrast, the FGF2 and FGFR mRNA expression in GC was very weak and without any regulatory change during follicle growth. Histological observation revealed that FGF2 protein was localised in theca tissue (cytoplasm of endothelial cells and pericytes) but not in GC. Our results suggest that VEGF and FGF families are involved in the proliferation of capillaries that accompanies the selection of the preovulatory follicle resulting in an increased supply of nutrients and precursors, and therefore supporting the growth of the dominant follicle.
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Abstract
Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and an inducer of angiogenesis. VEGF is also known as a vascular permeability factor because it can stimulate vascular permeability. In the rodent, increased uterine vascular permeability occurs at the sites of blastocysts with the onset of the attachment reaction. This is followed by stromal decidualization and angiogenesis. We examined the temporal and spatial expression of VEGF and its receptors, Flk-1 and Flt-1, in the mouse uterus during the peri-implantation period (days 1–8) using Northern and in situ hybridization to assess the involvement of VEGF in the process of implantation. Primarily, a major (≈4·2 kb) transcript for VEGF mRNA was detected in uterine poly(A) samples, except for the presence of two other minor (≈3·7 and 2·5 kb) transcripts in decidual samples. The steady-state levels of these transcripts did not vary much during the peri-implantation period, except for an increase in day-8 decidual samples. Results of in situ hybridization experiments demonstrated accumulation of VEGF mRNA in the luminal epithelium on days 1 and 2. In contrast, stromal cells exhibited a modest level of signals on day 3. On day 4, luminal epithelial cells and those in the subepithelial stromal bed accumulated VEGF mRNA. On days 5–7, a clear cell type-specific accumulation of this mRNA was noted. On day 5 after the initial attachment reaction, luminal epithelial and stromal cells immediately surrounding the blastocyst exhibited accumulation of VEGF mRNA. On days 6–8, the accumulation occurred in cells in the decidual bed at both the mesometrial and antimesometrial poles. The embryo, especially the trophoblast giant cells, also accumulated VEGF mRNA on day 8.
The expression of the VEGF receptors, Flk-1 and Flt-1, was also examined. A single transcript (≈6·5-7·0 kb) for Flk-1 mRNA and two transcripts (≈6·5 and 7·5 kb) for that of Flt-1 were detected in poly(A)+ uterine RNA samples. In situ hybridization studies showed accumulation of Flk-1 mRNA in a subset of cells in the stromal bed on day 4, but not in any uterine cell types on day 1. On days 5–8, cells in both the mesometrial and antimesometrial decidual beds exhibited accumulation of Flk-1 and Flt-1 mRNAs. Lectin binding (Dolichos biflorus agglutinin) was used to identify newly sprouting endothelial cells (angiogenesis), while an antibody to the von Willebrand factor (vWF) was employed to identify endothelial cells in general. The results suggest that vWF-positive stromal cells on day 4 and cells in the antimesometrial decidual bed on days 5–8 correlated with the expression of Flk-1 mRNA, as did the vWF- and lectin-positive cells in the mesometrial decidual bed. This implies that cells involved in angiogenesis at the mesometrial pole express the VEGF receptor mRNAs. In contrast, perhaps the endothelial cells of the existing blood vessels in the stromal bed on day 4 and those in the antimesometrial decidual bed on days 5–8 accumulated the receptor mRNAs, suggesting an involvement of VEGF in changes in vascular permeability. Flk-1 mRNA was also detected in embryonic tissues on day 8.
Collectively, the results suggest that VEGF participates in increased vascular permeability and/or angiogenesis occurring in the uterine vascular bed during implantation. Further, the data suggest that VEGF is involved in trophoblast differentiation and invasion, as well as in decidualization and placentation.
Journal of Endocrinology (1995) 147, 339–352
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. International Journal of Cancer 144 641 – 650 . ( https://doi.org/10.1002/ijc.31913 ) Malik S Day K Perrault I Charnock-Jones DS Smith SK 2006 Reduced levels of VEGF-A and MMP-2 and MMP-9 activity and increased TNF-alpha in menstrual
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potential for reduced insulin-independent adipocyte glucose uptake. EGFR and VEGFR EGF and related vascular endothelial growth factor (VEGF) signaling pathways regulate growth, survival, proliferation, and differentiation in mammalian cells ( Press
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A single, low-dose administration of a potent antiprogesterone such as mifepristone (RU486) in the early luteal phase results in inhibition of blastocyst implantation in primates. The aim of the present study was to examine the status of leukaemia inhibitory factor (LIF), transforming growth factor beta (TGF beta) and vascular endothelial growth factor (VEGF) in day 6 gestational endometrium of rhesus monkeys with or without exposure to a single dose (2 mg/kg body weight, s.c.) of mifepristone on day 2 after ovulation. Densitometric analyses of immunoblots of endometrial spent media revealed an increase (P < 0.01) in TGF beta pan (TGF beta 1, 2, 3 and 5) and a decrease (P < 0.01) in VEGF secretion from RU486-exposed endometrial samples compared with control samples. Secretory profiles for LIF, TGF beta 1 and TGF beta 1 LAP (latency associated peptide) remained unchanged in the two treatment groups. Morphometric analyses of immunohistochemical staining showed altered cell-specific distribution. TGF beta 1 (P < 0.01) and TGF beta pan (P < 0.02) were higher, while VEGF declined (P < 0.05) in endometrial glands of RU486-exposed endometria compared with control tissue samples. Stromal cell staining patterns for all experimental cytokines studied remained unchanged. In blood vessels, VEGF was found to be low (P < 0.05), while LIF (P < 0.05) and TGF beta 1 (P < 0.01) were higher in mifepristone-exposed endometrial samples compared with control tissue samples. Increased TGF beta secretion together with elevated levels of TGF beta in glandular epithelia and in blood vessels with no apparent change in stromal levels of TGF beta or in levels of TGF beta LAP in any endometrial compartment in the two treatment groups suggest an altered paracrine involvement of this cytokine and an enhanced activation of latent TGF beta in endometrium following mifepristone treatment. Higher levels of TGF beta in gland cells may result in dysregulated growth control and degenerative morphology. Also, higher levels of LIF and TGF beta together with lower levels of VEGF in the vascular compartment in mifepristone-exposed endometrium suggest that endometrial vascular physiology is a target of this anti-progestin during the peri-implantation stage. It is thus plausible that LIF, TGF beta and VEGF in the glandular and vascular compartments of implantation stage endometrium play important roles in rendering the endometrium receptive, and that early luteal phase treatment with an anti-progestin such as mifepristone affects the involvement of these cytokines resulting in endometrial contraception.
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Angiogenesis is the mechanism of blood vessel formation after the first few days of embryogenesis, and is essential for all tissue growth. In adults, angiogenesis occurs in the thyroid during disease processes including goitre, Graves' disease, thyroiditis and cancer. The molecular mechanisms controlling angiogenesis are becoming clearer, and therapy targeting these processes is coming closer to clinical fruition. Both promoters and inhibitors of angiogenesis have been identified in the thyroid, including vascular endothelial growth factor (VEGF), fibroblast growth factor, and thrombospondin. This commentary will review the understanding of the control of angiogenesis within the context of the thyroid gland, and review the pre-eminent role of VEGF as the angiogenic signal from the follicular cells to the endothelial cells.
