Expression of Angiopoietin-2 by Human Endometrial Endothelial Cells: Regulation by Hypoxia and Inflammation

Krikun, Graciela; Schatz, Frederick; Finlay, T.Y.; Kadner, Susan; Mesia, Augusto F.; Gerrets, Rene P.; Lockwood, Charles J.

doi:10.1006/bbrc.2000.3277

Cited by 91 publications

(74 citation statements)

References 22 publications

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“…This is consistent with our previously published results demonstrating that HEECs expressed Ang-2 mRNA and these levels were greatly increased by hypoxia. 15 In addition, we demonstrate that as expected, HEECs but not HESCs display a band for the Tie-2 receptor. As a control, we show that GAPDH was expressed by all cells (Figure 7).…”

Section: Effects Of Hypoxia and Oxidative Stress On Heec Ang-1 And Ansupporting

confidence: 76%

“…Peroxidase staining was conducted with the ABC elite kit from Vector Laboratories (Burlingame, CA) as described. 15 Goat polyclonal antibodies to Ang-2 were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Rabbit polyclonal antibody to Ang-1 was obtained from Alpha Diagnostic (San Antonio, TX).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Recently, our laboratory has shown that Ang-2 is expressed by endometrial endothelial cells and it is strongly up-regulated by hypoxia and the inflammatory agent phorbol myristate acetate. 15 In addition, a number of investigators have demonstrated that hypoxia also upregulates VEGF expression in endometrial stromal cells and glands. 16,17 Hypoxia is frequently followed by reperfusion and results in oxidative damage in the surrounding tissues.…”

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confidence: 99%

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Abnormal Uterine Bleeding during Progestin-Only Contraception May Result from Free Radical-Induced Alterations in Angiopoietin Expression

Krikun

Critchley

Schatz

et al. 2002

The American Journal of Pathology

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Abnormal uterine bleeding is the leading indication for discontinuation of long-term progestin-only contraceptives (LTPOCs). Histological sections of endometria from LTPOC-treated patients display abnormally enlarged blood vessels at bleeding sites.Paradoxically, a trend toward reduced endometrial perfusion in LTPOC users has been reported in these patients. We hypothesized that hypoxia/reperfusioninduced free radical production inhibits the expression of angiopoietin-1 (Ang-1), a vessel stabilizing factor, leaving unopposed the effects of endothelial Ang-2, a vessel-branching and permeability factor. Immunohistochemical studies confirmed selective decreases in stromal cell Ang-1 in LTPOC-exposed endometrium. To indirectly assess whether LTPOC enhances endometrial free radical production, immunostaining was conducted for the phosphorylated form of the stress-activated kinases SAPK/JNK and p38. These kinases were greatly increased in endometria from LTPOC-treated patients. Interestingly, the endothelial cells but not the stromal cells displayed enhanced immunostaining for the phosphorylated mitogen-activated kinase (pMAPK) after LTPOC treatment. To further examine the effects of progestin, hypoxia, and reactive oxygen species (ROS) on the regulation of Ang-1 and Ang-2 as well as the activation of MAPK, SAPK/JNK, and p38 by the relevant cell types, we conducted in vitro studies with cultured human endometrial stromal cells (HESCs) and human endometrial endothelial cells (HEECs). Cultures of HESCs were treated with vehicle control, estradiol (E 2 ), or with medroxyprogesterone acetate ؎ E 2 under hypoxic and normoxic conditions. Although medroxyprogesterone acetate but not E 2 increased Ang-1 expression, hypoxia greatly decreased Ang-1 protein and mRNA expression. In contrast, HESCs did not appear to express Ang-2 protein or mRNA. Conversely, cultured HEECs did not appear to express Ang-1, but expressed Ang-2, the levels of which were significantly increased by hypoxia. Hypoxia also induced the phosphorylation of SAPK/JNK and p38 in both cultured HESCs and HEECs. Moreover, ROS such as that observed after hypoxia/reperfusion resulted in the activation of SAPK/JNK and p38 in HESCs and HEECs and inhibited Ang-1 in cultured HESCs. These effects could be blocked by oxygen radical scavengers. Consistent with the in vivo studies, MAPK was activated after ROS treatment in HEECs but not in HESCs. Our findings suggest that LTPOC-induced endometrial bleeding occurs as a result of hypoxia/reperfusion-induced free radicals that directly damage vessels and alter the balance of Ang-1 and Ang-2 to produce the characteristic enlarged and permeable vessels that are prone to bleeding. Long-term progestin-only contraceptives (LTPOC) provide a highly practical solution to family-planning needs in developed and developing countries. Unfortunately, bleeding in the early months of treatment often results in the discontinuation of these otherwise safe and efficacious contraceptive methods. Several studies have shown that levonorgestrel (LN...

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Section: Effects Of Hypoxia and Oxidative Stress On Heec Ang-1 And Ansupporting

confidence: 76%

Section: Immunohistochemistrymentioning

confidence: 99%

mentioning

confidence: 99%

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Abnormal Uterine Bleeding during Progestin-Only Contraception May Result from Free Radical-Induced Alterations in Angiopoietin Expression

Krikun

Critchley

Schatz

et al. 2002

The American Journal of Pathology

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“…33 Ang2 mRNA is known to be up-regulated by VEGF, bFGF, hypoxia, and PMA. 24,31,34 We compared expression of Tie2 and Ang2 mRNA in response to various growth factors, serum, cytokines, and angiogenic inhibitors in normal HDMECs and HemECs ( Figure 4A). As expected, Tie2 mRNA was slightly enhanced by incubation for 8 hours in serum-free medium containing tumor necrosis factor-␣, but no difference in expression was observed between HemECs and HDMECs (data not shown).…”

Section: Dysregulated Expression Of Ang2 In Hemecsmentioning

confidence: 99%

Increased Tie2 Expression, Enhanced Response to Angiopoietin-1, and Dysregulated Angiopoietin-2 Expression in Hemangioma-Derived Endothelial Cells

Varughese

Brown

et al. 2001

The American Journal of Pathology

143

109

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Infantile hemangiomas are endothelial tumors that grow rapidly in the first year of life and regress slowly during early childhood. Although hemangiomas are well-known vascular lesions, little is known about the mechanisms that cause the excessive endothelial cell proliferation in these most common tumors of infancy. To investigate the molecular basis of hemangioma, we isolated endothelial cells from several proliferative-phase lesions and showed that these cells are clonal and exhibit abnormal properties in vitro

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“…Hypoxicinduced Ang-2 expression has also been reported in epithelial cells and glioma cells (5,16,17). Unlike HCT116 cells and human glioma cells, in which hypoxic stimulation directly induces Ang-2 (18), a decrease in both the oxygen concentration and the nutrient supply induced Ang-2 expression in the LoVo CRC cell line, which suggests that poor nutrition may be another stimulus of Ang-2 induction.…”

mentioning

confidence: 93%

Hypoxia-induced up-regulation of angiopoietin-2 in colorectal cancer

Yamamoto²,

Ogawa³

et al. 2006

Oncol Rep

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Abstract. Angiogenesis is a compensatory mechanism that enables malignant tumors to survive in an oxygen-deficient environment. To test our hypothesis that hypoxia stimulates the production of angiopoietin-2 (Ang-2) in colorectal cancer (CRC), we investigated the expression of Ang-2 in three cultured CRC cell lines, and in specimens from 11 CRC metastatic liver tumors. Hypoxia-induced Ang-2 mRNA expression was clearly evident in HCT116 cells that did not express Ang-2 under normoxic conditions. Ang-2 mRNA was detected only after 48 h in hypoxic serum-deprived cultures in a LoVo cell line, and under both normoxic and hypoxic conditions without any noticeable difference in the HT29 cells. There was a stepwise increase in Ang-2 expression from the periphery to the central part of the liver metastatic foci, whereas an inverse result was noted in tumor blood vessels, with a gradual decrease in CD31-positive ECs from the edge to the central region of the metastatic lesion. An expression pattern similar to Ang-2 was found in glucose transporter 1 (Glut-1), a known hypoxia-induced factor. These findings suggest that hypoxia plays an important role in inducing the expression of Ang-2 in CRC.

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Expression of Angiopoietin-2 by Human Endometrial Endothelial Cells: Regulation by Hypoxia and Inflammation

Cited by 91 publications

References 22 publications

Abnormal Uterine Bleeding during Progestin-Only Contraception May Result from Free Radical-Induced Alterations in Angiopoietin Expression

Abnormal Uterine Bleeding during Progestin-Only Contraception May Result from Free Radical-Induced Alterations in Angiopoietin Expression

Increased Tie2 Expression, Enhanced Response to Angiopoietin-1, and Dysregulated Angiopoietin-2 Expression in Hemangioma-Derived Endothelial Cells

Hypoxia-induced up-regulation of angiopoietin-2 in colorectal cancer

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