Stabilization of Vascular Endothelial Growth Factor mRNA by Hypoxia-Inducible Factor 1

Liu, Louis X.; Lu, Hsienwie; Luo, Yuxia; Date, Taro; Belanger, Adam J.; Vincent, Karen A.; Akita, Geoffrey Y.; Goldberg, Mark A.; Cheng, Seng H.; Gregory, Richard J.; Jiang, Canwen

doi:10.1006/bbrc.2002.6551

Cited by 121 publications

(77 citation statements)

References 45 publications

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“…71,72 HIF-1 may also be involved in this pathway. 73 It is not yet clear whether regulation of HIF-1 levels plays a role in the up-regulation of VEGF induced by TLR agonists in synergy with A 2A R agonists. While hypoxia may play a role in regulating macrophage expression of VEGF in wound healing, the pathway we have demonstrated here does not require hypoxia, but rather involves a synergistic interaction between G-protein-coupled receptors (the A 2A Rs) and members of the TLR receptor family that act as pattern recognition receptors for foreign organisms and their constituents.…”

Section: Discussionmentioning

confidence: 99%

An Angiogenic Switch in Macrophages Involving Synergy between Toll-Like Receptors 2, 4, 7, and 9 and Adenosine A2A Receptors

Pinhal‐Enfield

Ramanathan

Haskó

et al. 2003

The American Journal of Pathology

259

221

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Adenosine A 2A receptor (A 2A R) agonists synergize with Escherichia coli (E. coli) LPS [toll-like receptor (TLR)4 agonist] to up-regulate vascular endothelial growth factor (VEGF) expression in murine macrophages. Here, we demonstrate that TLR2, TLR7, and TLR9, but not TLR3 and TLR5 agonists, also synergize with A 2A R agonists and adenosine to up-regulate VEGF, while simultaneously strongly down-regulating TNF␣ expression. In the absence of adenosine or A 2A R agonists, Porphyromonas gingivalis (P. gingivalis) LPS and PAM 3 CAG (TLR2 agonists), resiquimod (R848) (TLR7 agonist), and non-methylated CpG DNA (TLR9 agonist) strongly up-regulate TNF␣ expression, with no effect on VEGF. In the presence of adenosine or A 2A R agonists, but not A 1 R agonists, TLR2, 4, 7, and 9 agonists strongly up-regulate VEGF expression, while simultaneously down-regulating TNF␣. C57BL/ 10ScN (TLR4 deletion mutant) macrophages produce TNF␣ in response to TLR2, 3, 7, and 9 agonists, but not the TLR4 agonist E. coli LPS. With adenosine or A 2A R agonists, TLR2, 7, and 9, but not TLR4 agonists, also synergistically up-regulate VEGF, while downregulating TNF␣ expression. Polyinosinic-polycytidilic acid (poly(I:C)) (TLR3 agonist) stimulates TNF␣ expression in macrophages from both C57BL/10ScSn and C57BL/10ScN mice, but has little effect on VEGF expression in the presence of adenosine or A 2A R agonists. R-flagellins from Serratia marcescens (S. marcescens) and Salmonella muenchen (S. muenchen) do not stimulate TNF␣ expression in either C57BL/ 10ScSn or C57BL10/ScN mice, and have no effect on VEGF production in the presence of adenosine or A We have shown previously that VEGF expression by murine macrophages is synergistically up-regulated by Escherichia coli (E. coli) lipopolysaccharide (LPS) acting through TLR4 receptors, and adenosine A 2A agonists acting through A 2A Rs. 3 Treatment of macrophages with 2-[p-(2-carboxylethyl)-phenylethyl amino]-5Ј-N-ethyl-carboxamido-adenosine (CGS21680) (a specific adenosine A 2A R agonist), or 5Ј-N-ethyl-carboxamido-adenosine (NECA) (a non-specific adenosine A 2 R agonist), together with E. coli LPS, strongly up-regulates VEGF expression above the level induced by CGS21680 or NECA alone, while LPS alone does not induce VEGF expression. This synergistic up-regulation is independent of hypoxia, NO, and protein kinase-A and is stronger than that induced by hypoxia alone. 3 Mammalian toll-like receptors (TLRs) are members of a family of proteins that resemble the Drosophila toll protein. 4,5 Toll plays a role in dorsal-ventral patterning in the developing fly embryo, and also plays a key role in regulating the innate immune response of adult flies to fungi. 4,5 In mammals, TLR receptors also play a key role in the innate immune response. TLR receptors respond to bacteria and bacterial products by transmitting a ligandinduced trans-membrane signal that induces the expression of cytokines such as TNF␣, IL-1,

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Section: Discussionmentioning

confidence: 99%

An Angiogenic Switch in Macrophages Involving Synergy between Toll-Like Receptors 2, 4, 7, and 9 and Adenosine A2A Receptors

Pinhal‐Enfield

Ramanathan

Haskó

et al. 2003

The American Journal of Pathology

259

221

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“…Under hypoxic conditions, HIF-1 can bind to 5' enhancer region of VEGF and promote the transcription and expression of VEGF [21] , hence increasing angiogenesis and blood supply of hypoxia area. On the other hand, HIF-1α also increases VEGF mRNA stability under hypoxic conditions [22] . Our data showed that expression of VEGF protein in the group with positive expression of HIF-1α mRNA was significantly higher than the group with negative expression of HIF-1α mRNA (P = 0.002).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

Zhang²,

Ru³

et al. 2007

WJG

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of HIF-1α and VEGF. The mean survival time and the 5-year survival rate in cases with positive expression HIF-1α and VEGF and MVD value ≥ 41.5/0.72 mm 2 were significantly lower than those with negative expression of HIF-1α and VEGF and MVD value < 41.5/0.72 mm 2 . CONCLUSION:Overexpression of HIF-1α is found in gastric carcinoma. HIF-1α may induce the angiogenesis in gastric carcinoma by upregulating the transcription of VEGF gene, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice. INTRODUCTIONAngiogenesis plays an important role in tumor growth and metastasis [1,2] . The formation of tumor microvessels is stimulated by angiogenic factors, especially vascular endothelial growth factor (VEGF) [3][4][5] . Hypoxia is related to tumor cell growth, differentiation, invasion and metastasis activity. In recent years, studies showed that hypoxia inducible factor-1 (HIF-1) played an important role in oxygen balance and tumor angiogenesis [6] . HIF-1 consists of α and β subunits, and HIF-1α is a key subunit of HIF activity regulated by hypoxia [1] . HIF-1 mRNA and protein overexpression was found in a variety of tumors, including breast cancer, prostate cancer, kidney cancer, rectal adenocarcinoma, etc [2,4,[7][8][9] . However, research on HIF-1α in gastric cancer was rarely reported. In the present study, BASIC RESEARCHUpregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma Abstract AIM:To investigate the implication of the hypoxia inducible factor HIF-1α mRNA in gastric carcinoma and its relation to the expression of vascular endothelial growth factor (VEGF) protein, tumor angiogenesis invasion/metastasis and the patient's survival. METHODS:In situ hybridization was used to examine expression of HIF-1α mRNA, and immunohistochemical staining was used to examine expression of VEGF protein and CD34 in 118 specimens from patients with gastric carcinoma. RESULTS:The positive rates of HIF-1α mRNA and VEGF protein were 49.15% and 55.92%, respectively. Positive expressions of HIF-1α and VEGF in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis were dramatically stronger than stage T1-T2 cases and those without vessel invasion, lymph node metastasis and distant metastasis. The mean microvascular density (MVD) in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis was significantly higher than stage T1-T2 tumors and those without vessel invasion, lymph node metastasis and distant metastasis. The mean MVD in tumors with positive HIF-1α and VEGF expression was significantly higher than that in tumors with negative HIF-1α and VEGF expression. The expression of HIF-1α was positively correlated with VEGF protein. There were positive correlations between MVD and expression

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“…25 One such mechanism is the initiation of vascular endothelial growth factor (VEGF) transcription and secretion to induce VEGF-dependent capillary growth to areas of tissue ischemia. 26 Because of the relationship between hypoxia, HIF-1 and VEGF, it is interesting to postulate that chronic hypoxia resulted in the synthesis and secretion of islet factors, such as vascular endothelial growth factor, which in part may have been responsible for the generation of the capillary network, suggesting an interesting further study.…”

Section: Resultsmentioning

confidence: 99%

Maintenance of aerobic metabolism increases immunoisolated islet survival

Stagner

Seelan²,

Parthasarathy³

2011

Islets

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Stabilization of Vascular Endothelial Growth Factor mRNA by Hypoxia-Inducible Factor 1

Cited by 121 publications

References 45 publications

An Angiogenic Switch in Macrophages Involving Synergy between Toll-Like Receptors 2, 4, 7, and 9 and Adenosine A2A Receptors

An Angiogenic Switch in Macrophages Involving Synergy between Toll-Like Receptors 2, 4, 7, and 9 and Adenosine A2A Receptors

Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

Maintenance of aerobic metabolism increases immunoisolated islet survival

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