UMLS:C0038187 - FACTA Search

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Query: UMLS:C0038187 (starvation)
24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Perfusion insufficiency, and the resultant hypoxia, often induces a compensatory neovascularization to satisfy the needs of the tissue. We have used multicellular tumor spheroids, simulating avascular microenvironments within a clonal population of glioma tumor cells, in conjunction with in situ analysis of gene expression, to study stress inducibility of candidate angiogenic factors. We show that expression of vascular endothelial growth factor (VEGF) is upregulated in chronically hypoxic niches (inner layers) of the spheroid and that expression is reversed when hypoxia is relieved by hyperoxygenation. Acute glucose deprivation--another consequence of vascular insufficiency--also activates VEGF expression. Notably, glioma cells in two distinct regions of the spheroid upregulated VEGF expression in response to hypoxia and to glucose starvation. Experiments carried out in cell monolayers established that VEGF is independently induced by these two deficiencies. Upon implantation in nude mice, spheroids were efficiently neovascularized. Concomitant with invasion of blood vessels and restoration of normoxia to the spheroid core, VEGF expression was gradually downregulated to a constitutive low level of expression, representing the output of nonstressed glioma cells. These findings show that stress-induced VEGF activity may compound angiogenic activities generated through the tumor "angiogenic switch" and suggest that stress-induced VEGF should be taken into account in any attempt to target tumor angiogenesis.
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PMID:Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. 753 42

We examined the role of vascular endothelial growth factor (VEGF) in preventing apoptosis in primary human umbilical vein endothelial (HUVE) cells. VEGF was capable of preventing serum starvation-induced apoptosis at concentrations between 10 and 100 ng/ml. The addition of VEGF to serum-starved HUVE cells led to a 5. 2-fold induction of Bcl-2 after 36 h and to a transient, 2.4-fold induction of A1 after a 7-h incubation, as quantitated by real time reverse transcriptase-polymerase chain reaction analysis. Western blot analysis demonstrated a 2-3-fold induction of Bcl-2 protein after 18-36 h of exposure to VEGF and a transient induction of A1 after 7 h of VEGF stimulation. Moreover, overexpression of Bcl-2 by means of transient biolistic transfection experiments of HUVE cells was sufficient to prevent endothelial cells from apoptotic cell death in the absence of VEGF. These findings indicate that Bcl-2 plays an important role in mediating the survival activity of VEGF on endothelial cells.
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PMID:Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. 958 77

Hypoxia is known to stimulate vascular growth by up-regulating vascular endothelial growth factor (VEGF), but little is known about the function of hypoxia in the development of the coronary vasculature, and the relationship between hypoxia and VEGF in this event. To test the effects of hypoxia and VEGF on coronary vasculogenesis/angiogenesis in the developing heart, ventricles from 6-day-old quail embryos were cultured on three-dimensional collagen gels. After 2 days of growth in normal medium and 1 day of starvation in low serum medium (0.5% fetal bovine serum), the heart explants were further cultured under various oxygen levels for another 24, 48, and 72 hr. Angioblasts and endothelial cells, which migrated out from the heart explants, were identified by QH1 antibody using immunofluorescence and confocal microscopy. In the normoxic culture environment, the endothelial cells began to proliferate and migrate out from the heart explants after 3 days of growth; they formed tubes mainly after another 72 hr. In contrast, this vascular growth was accelerated under hypoxic conditions, as evidenced by increased tube formation with significant differences observed at 48 hr. On the other hand, hyperoxia delayed this process. Reverse transcription-polymerase chain reaction results indicated that VEGF (including VEGF(122), VEGF(166), and VEGF(190)) was up-regulated in the heart explants under hypoxia and down-regulated under hyperoxia. VEGF neutralizing antibody added to the culture medium partially blocked this vascular growth. We conclude from this study that hypoxia can stimulate or up-regulate coronary vasculogenesis/angiogenesis and that VEGF signaling plays a major role in this event. Dev Dyn 1999;216:28-36.
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PMID:Stimulation of coronary vasculogenesis/angiogenesis by hypoxia in cultured embryonic hearts. 1047 63

Since the galactose-fed dog is an animal model that develops the advanced stage of proliferative retinopathy, the effects of vascular endothelial growth factor (VEGF) on cell growth, receptor expression and the activation of mitogen-activated protein (MAP) kinase pathway of dog retinal capillary endothelial cells were investigated. Dog retinal endothelial cells were cultured at 37 degrees C under 5% carbon dioxide atmosphere in CS-C medium supplemented with endothelial cell growth factor (ECGF). VEGF receptor expression was examined by RT-PCR, and activation of MAP kinase was examined with antibody against phospho-Elk-1 (Ser383). When growth factors were removed from the culture medium, cell survival of dog endothelial cells was significantly reduced. Addition of VEGF protected these cells from cell death induced by growth factor starvation. VEGF also enhanced tube formation in dog endothelial cells and increased the expression of two VEGF receptors, Flt-1 and KDR/Flk-1. Cells treated with VEGF also displayed the phosphorylation of the transcription factor, Elk-1. Addition of the tyrosine kinase inhibitor, genistein, eliminated VEGF-induced cell growth and Elk-1 phosphorylation. These data confirm that cell growth and tube formation of dog retinal capillary endothelial cells are stimulated by VEGF. VEGF also increases the expression of the receptors, KDR and Flt-1, and activates the p44/42 MAP kinase pathway.
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PMID:Vascular endothelial growth factor (VEGF) enhances the expression of receptors and activates mitogen-activated protein (MAP) kinase of dog retinal capillary endothelial cells. 1097 34

Evidence suggests the involvement of growth hormone (GH), insulin-like growth factor I (IGF-I) and somatostatin in the pathology associated with diabetic retinopathy. We examined the effect of IGF-I on human retinal endothelial cell (HREC) survival following high glucose exposure and serum starvation, examined the signalling pathways mediating the protective effect of IGF-I on HREC, and characterized somatostatin receptor-induced retinal endothelial cell death. IGF-I (10 ng/ml) protected HREC from apoptosis induced by high glucose and serum starvation. Wortmannin, a specific inhibitor of phosphotidylinositol-3-kinase, blocks the ability of IGF-I to protect HREC from apoptosis. Incubation of HREC in serum-free medium caused a time-dependent increase in c-Jun N-terminal kinase (JNK) activity, and continuous culture of HREC in the presence of IGF-I or vascular endothelial growth factor (VEGF) prevented JNK activation and arrested apoptosis. Activation of tyrosine kinase receptors results in extracellular signal-related kinase (ERK) activation and activation of ERK is required for proliferation. Both IGF-I and VEGF produced a time- and concentration-dependent increase in the activation of ERK. Type 2 and type 3 somatostatin receptors have been implicated in cell-cycle arrest and apoptosis. Activation of the type 3 receptor in HREC resulted in cell death. These studies suggest that IGF-I is critical for HREC survival, and that somatostatin analogues acting through the type 3 receptor have direct effects on retinal endothelial cells. Furthermore, it appears that the therapeutic efficacy of somatostatin analogues lies not only in systemic inhibition of GH, but also in modulating local growth factor effects.
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PMID:Modulation of retinal endothelial cell behaviour by insulin-like growth factor I and somatostatin analogues: implications for diabetic retinopathy. 1152 89

White adipose tissue has distinctive angiogenic properties. White adipocytes are capable of producing vascular endothelial growth factor (VEGF) in response to insulin and catecholamines. Recognizing the dual functions of adipose tissue as an endocrine/metabolic organ and fuel storage depot with an inimitable ability to adjust its organ mass, our aim was to determine whether fasting would affect adipocyte VEGF 165 production. Rats were fed ad libitum, then fasted for 24 hours, and then refed after the 24-hour fast. The isolated white adipocytes from each group and blood endocrine/metabolic profiles were examined at each stage, yielding three sets of results. Using cultured adipocytes, fasting caused a two-fold increase in VEGF 165 formation compared to fed rats that normalized after refeeding. Likewise, freshly prepared adipocytes manifested a three-fold augmentation in adipocyte VEGF 165 mRNA expression and a 60 % increase the transcriptional regulator hypoxia-inducible factor 1 (HIF-1alpha) that normalized after refeeding. Blood studies revealed the expected fasting-related alterations in glucose, beta-hydroxybutyrate and corticosterone. Plasma VEGF concentrations were attenuated by 26 % with fasting, and did not normalize with refeeding. Multiple linear regression analyses uncovered statistically significant inverse correlations between plasma VEGF and blood beta-hydroxybutyrate or serum corticosterone. Blood glucose, in contrast, correlated directly with plasma VEGF. We will discuss the potential role of enhanced adipocyte VEGF formation during starvation in light of the known actions of this factor on vascular endothelial mitogenesis and permeability.
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PMID:Nutritional regulation of white adipocyte vascular endothelial growth factor (VEGF). 1277 63

The gene of phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) has been implicated as an oncogene in ovarian cancer [L. Shayesteh et al., Nat. Genet., 21: 99-102, 1999]. In this study, we examined the expression of PIK3CA mRNA and its p110alpha protein product in human ovarian carcinoma and investigated its role in regulating angiogenesis via vascular endothelial growth factor (VEGF). PIK3CA mRNA was detected in 66.6% of stage I and 93.9% of advanced stage ovarian cancer specimens and in all 17 ovarian cancer cell lines. PIK3CA mRNA levels were significantly higher in invasive carcinomas compared with benign and low malignant potential neoplasms (P = 0.007), but no significant difference was seen between early and advanced stage carcinomas (P = 0.812). Strong expression of immunoreactive p110alpha was detected in tumor cells and/or stroma endothelium. PIK3CA expression in vivo positively correlated, both at the mRNA and the protein level, with the expression of VEGF as well as with the extent of microvascular development. Furthermore, PIK3CA mRNA overexpression positively correlated with increased proliferation and decreased apoptosis of tumor cells in vivo. In vitro, PIK3CA expression positively correlated with the expression of VEGF in ovarian cancer cells, whereas the phosphatidylinositol 3'-kinase inhibitor Ly294002 reduced both the constitutive and inducible expression of hypoxia-inducible factor-1alpha at the mRNA and protein levels and abrogated VEGF up-regulation by glucose starvation. Furthermore, Ly294002 suppressed cell proliferation and, at higher doses, induced marked apoptosis in ovarian cancer cells. Collectively, these data strongly indicate that PIK3CA supports ovarian cancer growth through multiple and independent pathways affecting cell proliferation, apoptosis and angiogenesis, and plays an important role in ovarian cancer progression.
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PMID:The oncogene phosphatidylinositol 3'-kinase catalytic subunit alpha promotes angiogenesis via vascular endothelial growth factor in ovarian carcinoma. 1287 30

Hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of vascular endothelial growth factor (VEGF) and other hypoxia-responsive genes. Transgenic expression of a constitutively stable HIF-1alpha mutant increases the number of vascular vessels without vascular leakage, tissue edema, or inflammation. This study aimed to investigate the molecular basis by which HIF-1 mediates the angiogenic response to hypoxia. In primary human endothelial cells, hypoxia, desferrioxamine, or infection with Ad2/HIF-1alpha/VP16, an adenoviral vector encoding a constitutively stable hybrid form of HIF-1alpha, increased the mRNA and protein levels of VEGF, angiopoietin-2 (Ang-2), and angiopoietin-4 (Ang-4). Infection with Ad2/CMVEV (a control vector expressing no transgene) had no effect. Angiopoietin-1 (Ang-1) expression was not detected in human endothelial cells. Ang-4 was also induced by hypoxia or Ad2/HIF-1alpha/VP16 in human cardiac cells, whereas Ang-1 expression remained unchanged. Recombinant Ang-4 protein protected endothelial cells against serum starvation-induced apoptosis and increased cultured endothelial cell migration and tube formation. Ad2/HIF-1alpha/VP16 stimulated endothelial cell proliferation and tube formation. Hypoxia- or Ad2/HIF-1alpha/VP16-induced tube formation was significantly reduced by a Tie-2 inhibitor. These results suggest that HIF-1 mediates the angiogenic response to hypoxia by upregulating the expression of multiple angiogenic factors. Ang-4 can function similarly as Ang-1 and substitute for Ang-1 to participate in hypoxia-induced angiogenesis. Activation of the angiopoietin/Tie-2 system may play a role in the ability of HIF-1 to induce hypervascularity without excessive permeability.
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PMID:Hypoxia-inducible factor-1 mediates activation of cultured vascular endothelial cells by inducing multiple angiogenic factors. 1295 44

Hematopoietic progenitor cell transplantation can contribute to revascularization of ischemic tissues. Yet, the optimal cell population to be transplanted has yet to be determined. We have compared the therapeutic potential of two subsets of human cord blood CD34+ progenitors, either expressing the VEGF-A receptor 2 (KDR) or not. In serum-free starvation culture, CD34+KDR+ cells reportedly showed greater resistance to apoptosis and ability to release VEGF-A, as compared with CD34+KDR- cells. When injected into the hind muscles in immunodeficient SCIDbg mice subjected to unilateral ischemia, a low number (10(3)) of CD34+KDR+ cells improved limb salvage and hemodynamic recovery better than a larger dosage (10(4)) of CD34+KDR- cells. The neovascularization induced by KDR+ cells was significantly superior to that promoted by KDR- cells. Similarly, endothelial cell apoptosis and interstitial fibrosis were significantly attenuated by KDR+ cells, which differentiated into mature human endothelial cells and also apparently skeletal muscle cells. This study demonstrates that a low number of CD34+KDR+ cells favors reparative neovascularization and possibly myogenesis in limb ischemia, suggesting the potential use of this cell population in regenerative medicine.
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PMID:Transplantation of low dose CD34+KDR+ cells promotes vascular and muscular regeneration in ischemic limbs. 1534 95

n-3 Polyunsaturated fatty acids (PUFAs) inhibit the development of microvessels in mammary tumors growing in mice. Human colorectal tumors produce vascular endothelial growth factor (VEGF) whose expression is up-regulated in tumor cells by both cyclooxygenase-2 (COX-2) and PGE(2) and directly correlated to neoangiogenesis and clinical outcome. The goal of this study was to examine the capability of n-3 PUFAs to regulate VEGF expression in HT-29 human colorectal cells in vitro and in vivo. Constitutive VEGF expression was augmented in cultured HT-29 cells by serum starvation and the effects of eicosapentaenoic (EPA) or docosahexaenoic acid (DHA) on VEGF, COX-2, phosphorylated extracellular signal-regulated kinase (ERK)-1 and -2 and hypoxia-inducible-factor 1-alpha (HIF-1alpha) expression and PGE(2) levels were assessed. Tumor growth, VEGF, COX and PGE(2) analysis were carried out in tumors derived from HT-29 cells transplanted in nude mice fed with either EPA or DHA. Both EPA and DHA reduced VEGF and COX-2 expression and PGE(2) levels in HT-29 cells cultured in vitro. Moreover, they inhibited ERK-1 and -2 phosphorylation and HIF-1alpha protein over-expression, critical steps in the PGE(2)-induced signaling pathway leading to the augmented expression of VEGF in colon cancer cells. EPA always showed higher efficacy than DHA in vitro. Both fatty acids decreased the growth of the tumors obtained by inoculating HT-29 cells in nude mice, microvessel formation and the levels of VEGF, COX-2 and PGE(2) in tumors. The data provide evidence that these n-3 PUFAs are able to inhibit VEGF expression in colon cancer cells and suggest that one possible mechanism involved may be the negative regulation of the COX-2/PGE(2) pathway. Their potential clinical application as anti-angiogenic compounds in colon cancer therapy is proposed.
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PMID:n-3 PUFAs reduce VEGF expression in human colon cancer cells modulating the COX-2/PGE2 induced ERK-1 and -2 and HIF-1alpha induction pathway. 1535 33

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