Hypoxic Regulation of Angiopoietin-2 Expression in Endothelial Cells

Pichiule, Paola; Chávez, Juan C.; LaManna, Joseph Charles

doi:10.1074/jbc.m305146200

Cited by 179 publications

(138 citation statements)

References 60 publications

(65 reference statements)

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“…21 VEGF and bFGF are the major growth factors that activate angiogenesis and also induce Ang2. 22,23 We have found that both VEGF 165 (V; Figure 1) and bFGF (F; Figure 1) induce Ang2, with bFGF exhibiting greater potency. Thus, the maximal induction of 3.5-fold was achieved by VEGF at a concentration of 50 ng/mL, while bFGF-mediated induction of Ang2 (25.0 Ϯ 1.6-fold) was detected at a concentration of approximately 100 ng/mL ( Figure 1A).…”

Section: Regulation Of Angiogenesis By -3 Pufas 3515mentioning

confidence: 94%

Modulation of angiogenesis by ω-3 polyunsaturated fatty acids is mediated by cyclooxygenases

Szymczak

Murray

Petrović

2008

Blood

112

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The potential role of dietary fats in cancer is attracting considerable interest within the community. Both epidemiologic and experimental findings suggest that omega-3 polyunsaturated fatty acids (-3 PUFAs), which are almost absent from typical Western diets, exert protective effects against cancer progression, although the precise mechanism of this suppression remains unknown. One of the potential targets for -3 PUFAs in cancer suppression is angiogenesis, a process of new blood vessel formation within rapidly growing tumors. Here, we demonstrate that -6 PUFAs stimulate and -3 PUFAs inhibit major proangiogenic processes in human endothelial cells, including the induction of angiopoietin-2 (Ang2) and matrix metalloprotease-9, endothelial invasion, and tube formation, that are usually activated by the major -6 PUFA arachidonic acid. The cyclooxygenase (COX)-mediated conversion of PUFAs to prostanoid derivatives participated in modulation of the expression of Ang2. Thus, the -6 PUFA-derived prostaglandin E2 augmented, whereas the -3 PUFA-derived prostaglandin E3 suppressed the induction of Ang2 by growth factors. Our findings are consistent with the suggestion that PUFAs undergo biotransformation by COX-2 to lipid mediators that modulate tumor angiogenesis, which provides new insight into the beneficial effects of IntroductionInitial reports of the beneficial effects of long-chain omega-3 polyunsaturated fatty acids (-3 PUFAs) in human physiology occurred in the mid-1970s with observations that the dietary intake of fish-derived lipids correlated with decreased incidence of cardiovascular diseases and cancer. Thus, the lower incidence of cardiac diseases in the Inuit population has been attributed to the content of fish, which are high in -3 PUFAs, in the Inuit diet. 1 In another seminal study, Japanese women were found to have a lower risk of breast cancer compared with their counterparts in other developed countries. 2 When Japanese women migrated to countries with higher prevalence of breast cancer and adopted local diets, the incidence of disease more closely resembled that of the local population, thus indicating the importance of environmental factors. Rapidly, the interest of researchers focused on the possible protective effects of oily fish-derived -3 PUFAs, especially eicosapentaenoic acid (EPA; C20:5 n-3) and docosahexaenoic acid (DHA; C22:6 n-3). These -3 PUFAs are produced by phytoplankton and are accumulated in the fatty tissue of fish. -6 PUFAs, which are derived principally from animal fat and include arachidonic acid (AA; C20:4 n-6), and -3 PUFAs are both essential for mammals, since they cannot be synthesized and must be consumed in diet.The mechanistic information underpinning the inhibitory effects of -3 PUFA intake on disease development is deficient. Both -6 and -3 PUFAs have a number of critical homeostatic functions. 3 As constituents of structural phospholipids of the cell membrane they influence membrane fluidity, modulate intracellular signaling pathways, and modify cell-cell interacti...

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Section: Regulation Of Angiogenesis By -3 Pufas 3515mentioning

confidence: 94%

Modulation of angiogenesis by ω-3 polyunsaturated fatty acids is mediated by cyclooxygenases

Szymczak

Murray

Petrović

2008

Blood

112

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“…The upregulation of Ang-2 during hypoxia and during reoxygenation is due to induction of cyclooxygenase-2 enzyme activity in brain endothelial cells (Pichiule et al, 2004). This enzyme is responsible for metabolism of arachidonic acid to prostaglandin E2, which induces Ang-2 production.…”

Section: Deadaptation and Agingmentioning

confidence: 99%

Structural and functional adaptation to hypoxia in the rat brain

LaManna

Chávez

Pichiule

2004

Journal of Experimental Biology

Self Cite

174

162

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Chronic exposure to a hypoxic environment leads to structural and functional adaptations in the rat brain. One significant adaptation is a decrease in intercapillary distances through a near doubling of the capillary density, which begins after about 1 week of hypoxic exposure and is completed by 3 weeks. Hypoxic angiogenesis is controlled by activation of downstream genes by Hypoxia Inducible Factor-1 and Angiopoietin-2. The processes that increase capillary density are reversible upon restoration of the ambient oxygen concentration. Capillary regression, which also occurs over a 3-week period, is accomplished through activation of apoptosis. The implication from these observations is that the brain naturally functions in a low, but controlled, oxygen environment. Acute imbalances in oxygen delivery and metabolic demand are addressed through changes in blood flow; persistent imbalances activate mechanisms that adjust capillary density. The mechanisms that control these processes decline with age.

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“…Produced by vascular smooth muscle cells (SMCs) and precursor pericytes, Ang-1-induced activation of the Tie2 receptor promotes quiescence and structural integrity of mature vessels, thus protecting the endothelium from activation by cytokines and growth factors [18][19][20][21][22][23]. In contrast, Ang-2 disrupts the constitutive Ang-1/Tie2 signaling by preventing Ang-1 from binding to the common receptor [15,[24][25][26]. Increased Ang-2 release from endothelial Weibel-Palade bodies upon stimulation of the endothelium with for instance hypoxia [24] seems to be essential for tumor angiogenesis [27].…”

Section: Introductionmentioning

confidence: 99%

Shedding of the endothelial receptor tyrosine kinase Tie2 correlates with leukemic blast burden and outcome after allogeneic hematopoietic stem cell transplantation for AML

et al. 2010

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Angiogenesis plays an important role in the growth and viability of hematologic malignancies. Emerging data suggest a crucial involvement of the endothelial-specific Tie2 receptor and its antagonistic ligand Angiopoietin-2 (Ang-2) in this process. The purpose of this study was to elucidate whether the soluble domain of the Tie2 receptor (sTie2) predicts outcome in patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Serum levels of sTie2 and Ang-2 were measured by ELISA in 181 AML patients before conditioning for HSCT. The median follow-up time was 22 months after HSCT. Pre-HSCT sTie2 levels were significantly higher in patients (median 2.2 (range 1.8-3.0) ng/mL) compared to healthy controls (1.3 (0.9-1.6); p<0.0001). Elevated sTie2 levels were independently associated with active AML but did not relate to cytogenetics/mutational status before transplantation. Logistic regression analysis identified elevated sTie2 (odds ratio (OR) 3.07 (95% confidence interval (CI; 1.56-6.04), p=0.001) as a strong predictor for disease relapse and poor overall survival after HSCT. In a multimarker approach the highest risk for relapse was observed in patients with both elevated sTie2 and elevated Ang-2 (OR 4.07, (95% CI 1.79-9.25) p<0.0001), as well as patients with both elevated Ang-2 and elevated bone marrow blast count (OR 4.16,) p<0.0001). Elevated serum sTie2 levels were related to active leukemia, correlated with the percentage of leukemic blasts in the bone marrow, and independently predicted relapse in AML patients after allogeneic HSCT. Furthermore, our data indicate that Tie2 shedding and Ang-2 release seem to reflect overlapping, but nevertheless distinctive features in leukemia-associated neoangiogenesis.

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Hypoxic Regulation of Angiopoietin-2 Expression in Endothelial Cells

Cited by 179 publications

References 60 publications

Modulation of angiogenesis by ω-3 polyunsaturated fatty acids is mediated by cyclooxygenases

Modulation of angiogenesis by ω-3 polyunsaturated fatty acids is mediated by cyclooxygenases

Structural and functional adaptation to hypoxia in the rat brain

Shedding of the endothelial receptor tyrosine kinase Tie2 correlates with leukemic blast burden and outcome after allogeneic hematopoietic stem cell transplantation for AML

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