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PubMedDate not supplied

The hemostatic system and angiogenesis in malignancy.

Coagulopathy and angiogenesis are among the most consistent host responses associated with cancer. These two respective processes, hitherto viewed as distinct, may in fact be functionally inseparable as blood coagulation and fibrinolysis, in their own right, influence tumor angiogenesis and thereby contribute to malignant growth. In addition, tumor angiogenesis appears to be controlled through both standard and non-standard functions of such elements of the hemostatic system as tissue factor, thrombin, fibrin, plasminogen activators, plasminogen, and platelets. "Cryptic" domains can be released from hemostatic proteins through proteolytic cleavage, and act systemically as angiogenesis inhibitors (e.g., angiostatin, antiangiogenic antithrombin III aaATIII). Various components of the hemostatic system either promote or inhibit angiogenesis and likely act by changing the net angiogenic balance. However, their complex influences are far from being fully understood. Targeted pharmacological and/or genetic inhibition of pro-angiogenic activities of the hemostatic system and exploitation of endogenous angiogenesis inhibitors of the angiostatin and aaATIII variety are under study as prospective anti-cancer treatments.

Animals↗
PubMed2003

Expression of an Ets-1 dominant-negative mutant perturbs normal and tumor angiogenesis in a mouse ear model.

We and others have shown that members of the Ets family of transcription factors are involved in morphogenic properties of endothelial cells in vitro. To investigate the role of these factors in the transcriptional regulation of angiogenesis in vivo, we set up a nontraumatic model that allows daily macroscopic examination of both growth factor- and tumor-induced angiogenesis in mouse ears. In the same animal, we were thus able to record variations in the patterns of neovessels induced and cell populations recruited by the angiogenic factors FGF-2 and VEGF. In this model, inhibition of FGF-2-induced angiogenesis by the pharmacological compound TNP-470 was readily observed, demonstrating that the mouse ear model is also useful in the evaluation of antiangiogenic strategies. Our functional analysis of Ets transcription factors activity utilized a competitor protein, Ets1-DB, a dominant negative Ets1 mutant lacking the transactivation domain. Retrovirus-mediated expression of Ets1-DB inhibited FGF-2-induced angiogenesis, while the expression of Ets1-DB in cancerous and stromal cells disturbed tumor-induced angiogenesis. These results illustrate the value of the ear model and highlight the role of Ets family members in the transcriptional regulation of tumor angiogenesis.

Animals↗
PubMed2000

Angiogenesis and vascular regression in the ovary.

Angiogenesis is prominent during development and downregulated in the adult. Strictly controlled angiogenesis in the healthy adult occurs cyclically in the ovary and corpus luteum, which therefore make an excellent model with which to study vascular growth. Dysfunctional or uncontrolled angiogenesis is involved in a number of diseases and is responsible for growth and dissemination of tumours. This review focuses on the following aspects of the ovary: the gross and microscopical anatomy of the blood vessels, described mainly--but not exclusively--in the bovine; vascularization of the follicle before and after ovulation; angiogenesis in the developing and the mature corpus luteum as well as in the corpus luteum of pregnancy. The potential mechanisms of vascular regression during luteolysis and the potential role of vascular growth in dominance and atresia of follicles will be described. Furthermore, recent research on ovarian angiogenic and potential anti-angiogenic factors including fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), angiopoietin and metalloproteinase inhibitor will be presented. Finally, the role of hormones including FSH, LH, sexual steroids, prostaglandins, prolactin, oxytocin and activin/inhibin in ovarian angiogenesis will be summarized. Future research is likely to yield valuable information that can contribute to the development of novel therapeutic strategies for the treatment of diseases characterized by disregulated angiogenesis and vascular regression.

Adult↗
PubMed1999

Role of vascular endothelial growth factor in the regulation of angiogenesis.

Compelling evidence indicates that vascular endothelial growth factor (VEGF) is a fundamental regulator of normal and abnormal angiogenesis. The loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF plays also a critical role in kidney development, and its inactivation during early postnatal life results in the suppression of glomerular development and kidney failure. Recent evidence indicates that VEGF is also essential for angiogenesis in the female reproductive tract and for morphogenesis of the epiphyseal growth plate and endochondral bone formation. Substantial experimental evidence also implicates VEGF in pathological angiogenesis. Anti-VEGF monoclonal antibodies or other VEGF inhibitors block the growth of several human tumor cell lines in nude mice. Furthermore, the concentrations of VEGF are elevated in the aqueous and vitreous humors of patients with proliferative retinopathies such as the diabetic retinopathy. In addition, VEGF-induced angiogenesis results in a therapeutic benefit in several animal models of myocardial or limb ischemia. Currently, both therapeutic angiogenesis using recombinant VEGF or VEGF gene transfer and inhibition of VEGF-mediated pathological angiogenesis are being pursued clinically.

Animals↗
PubMed2003

The role of plasminogen in angiogenesis in vivo.

UNLABELLED: Plasminogen, by virtue of its role in the degradation of extracellular matrix proteins and by facilitation of cell migration, may contribute to angiogenesis. OBJECTIVE: the purpose of this study was to evaluate the contribution of plasminogen to angiogenesis in vivo. METHODS: Angiogenesis was assessed in gene-targeted mice with deficiencies of plasminogen, urokinase plasminogen activator (uPA), and urokinase receptor (uPAR) in a mouse corneal model. In wild-type mice, female and young mice showed a trend toward increased angiogenesis compared to males and old mice. Because of this influence of age and gender on angiogenesis, young, female mice (6-13 weeks of age) were used for this study. RESULTS: In response to angiogenic stimulation by basic fibroblast growth factor (bFGF), uPA deficient mice exhibited a decrease in new vessel formation as reflected by vessel length (0.47 in control vs. 0.33 mm in uPA-/- mice, P = 0.043), but new vessel formation was not altered (P = 0.107) in the uPAR deficient mice compared to control mice. A significantly decreased angiogenic response of new vessel formation to both vascular endothelial growth factor (VEGF) (P < 0.02) and bFGF (P < 0.007) was observed in Plg deficient (Plg-/-) mice (VEGF - 0.36 mm, bFGF - 0.67 mm) compared to Plg+/+ mice (VEGF - 0.56 mm, bFGF - 0.85 mm). CONCLUSIONS: These results demonstrate the importance of plasminogen, as well as of uPA, in angiogenesis in vivo.

Animals↗
PubMed2002

Vascularisation of tissue-engineered grafts: the regulation of angiogenesis in reconstructive surgery and in disease states.

Angiogenesis (the formation of new blood vessels) is essential for the growth of new tissue, tissue repair and wound healing. Tissue engineering, the construction of new tissue and organs for reparative purposes, relies on angiogenesis for the vascularisation of these new grafts. In tissue engineering, the emphasis to date has been on vascularisation of newly constructed tissue grafts by an extrinsic blood supply, and relatively little attention has been given to the possibility of building these grafts around an intrinsic blood supply. However, there are many disease processes, notably tumour growth, where excess angiogenesis can be a major problem. The purposes of this review are, first, to examine various methods of vascularising tissue-engineered grafts, and, second, to compare the role of angiogenesis in tissue engineering, where stimulation of angiogenesis is paramount, with pathological states, such as tumour growth, where angiogenesis needs to be inhibited.

Artificial Organs↗
PubMed2002

VEGF-mediated angiogenesis of human pheochromocytomas is associated to malignancy and inhibited by anti-VEGF antibodies in experimental tumors.

BACKGROUND: Pheochromocytomas are well-vascularized tumors of the adrenal medulla. In human pheochromocytomas, angiogenesis has been associated with tumor progression. The mechanisms, however, are unknown. METHODS: Surgical specimens of benign, invasive, and metastatic human pheochromocytomas (n = 10/5/5) were immunostained for vascular endothelial growth factor (VEGF) and CD34, to determine VEGF expression and microvessel density (vascular surface density, [VSD]). In PC12-pheochromocytoma cells, VEGF messenger RNA and protein were analyzed by Northern blotting and enzyme immunoassay; biologic activity by human umbilical vein endothelial cell-proliferation assay. Inhibition of angiogenesis of PC12 xenografts by 2 neutralizing anti-VEGF antibodies (C20-pAB, M461-mAB) was evaluated by VEGF expression, VSD, and mitotic activity. RESULTS: VEGF expression and VSD were significantly higher in metastatic pheochromocytomas (VEGF 37.1 +/- 10.9% vs 20.7 +/- 9%, VSD 26.2 +/- 8 vs 13.5 +/- 3.3 1/mm). VEGF messenger RNA and protein were confirmed in PC12 cells and stimulated by nerve growth factor. Conditioned PC12 medium increased human umbilical vein endothelial cell proliferation more than 2-fold. Xentrotransplanted PC12 cells had marked VEGF expression and angiogenesis, which was inhibited by anti-VEGF antibodies (VEGF-expression by 29 and 38%, VSD by 43 and 46%, P <.05). CONCLUSION: Higher VEGF expression and microvessel density in malignant pheochromocytomas suggest VEGF-mediated angiogenesis to be related to tumor progression. Angiogenesis of PC12 xenografts is mediated by VEGF. Neutralizing anti-VEGF antibodies inhibit angiogenesis in experimental pheochromocytomas and may have potential for treating nonresectable pheochromocytomas.

Adrenal Gland Neoplasms↗
PubMed2000

Opioid growth factor modulates angiogenesis.

OBJECTIVE: Induced angiogenesis has recently been attempted as a therapeutic modality in patients with occlusive arterial atherosclerotic disease. We investigated the possible role of endogenous opioids in the modulation of angiogenesis. METHODS: Chick chorioallantoic membrane was used as an in vivo model to study angiogenesis. Fertilized chick eggs were incubated for 3 days, explanted, and incubated for an additional 2 days. Three-millimeter methylcellulose disks were placed on the surface of the chorioallantoic membrane; each disk contained opioid growth factor ([Met(5)]-enkephalin; 5 microgram), the short-acting opioid receptor antagonist naloxone (5 microgram), opioid growth factor and naloxone together (5 microgram of each), the long-acting opioid antagonist naltrexone (5 microgram), or distilled water (control). A second series of experiments was performed with distilled water, the angiogenic inhibitor retinoic acid (1 microgram), and vascular endothelial growth factor (1 microgram) to further evaluate our model. The developing vasculature was imaged 2 days later with a digital camera and exported to a computer for image analysis. Total number of blood vessels, total vessel length, and mean vessel length were measured within a 100-mm(2) region surrounding each applied disk. Immunocytochemical analysis was performed with antibodies directed against opioid growth factor and its receptor (OGFr). RESULTS: Opioid growth factor had a significant inhibitory effect on angiogenesis, both the number of blood vessels and the total vessel length being decreased (by 35% and 20%, respectively) in comparison with control levels (P <.005). The simultaneous addition of naloxone and opioid growth factor had no effect on blood vessel growth, nor did naloxone alone. Chorioallantoic membranes exposed to naltrexone displayed increases of 51% and 24% in blood vessel number and length, respectively, in comparison with control specimens (P <.005). These results indicate that the opioid growth factor effects are receptor mediated and tonically active. Immunocytochemistry demonstrated the presence of both opioid growth factor and OGFr within the endothelial cells and mesenchymal cells of the developing chorioallantoic membrane vessel wall. Retinoic acid significantly reduced the number and the total length of blood vessels, whereas vascular endothelial growth factor increased both the number and the length of blood vessels in comparison with the controls (P <.0001). The magnitude of opioid growth factor's effects were comparable to those seen with retinoic acid, whereas inhibition of opioid growth factor with naltrexone induced an increase in total vessel length comparable to that for vascular endothelial growth factor. CONCLUSIONS: These results demonstrate for the first time that endogenous opioids modulate in vivo angiogenesis. Opioid growth factor is a tonically active peptide that has a receptor-mediated action in regulating angiogenesis in developing endothelial and mesenchymal vascular cells.

Allantois↗
PubMed2001

Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability.

Nitric oxide (NO) plays a critical role in vascular endothelial growth factor (VEGF)-induced angiogenesis and vascular hyperpermeability. However, the relative contribution of different NO synthase (NOS) isoforms to these processes is not known. Here, we evaluated the relative contributions of endothelial and inducible NOS (eNOS and iNOS, respectively) to angiogenesis and permeability of VEGF-induced angiogenic vessels. The contribution of eNOS was assessed by using an eNOS-deficient mouse, and iNOS contribution was assessed by using a selective inhibitor [l-N(6)-(1-iminoethyl) lysine, l-NIL] and an iNOS-deficient mouse. Angiogenesis was induced by VEGF in type I collagen gels placed in the mouse cranial window. Angiogenesis, vessel diameter, blood flow rate, and vascular permeability were proportional to NO levels measured with microelectrodes: Wild-type (WT) > or = WT with l-NIL or iNOS(-/-) > eNOS(-/-) > or = eNOS(-/-) with l-NIL. The role of NOS in VEGF-induced acute vascular permeability increase in quiescent vessels also was determined by using eNOS- and iNOS-deficient mice. VEGF superfusion significantly increased permeability in both WT and iNOS(-/-) mice but not in eNOS(-/-) mice. These findings suggest that eNOS plays a predominant role in VEGF-induced angiogenesis and vascular permeability. Thus, selective modulation of eNOS activity is a promising strategy for altering angiogenesis and vascular permeability in vivo.

Animals↗
PubMed2006

Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy.

We describe that galectin-1 (gal-1) is a receptor for the angiogenesis inhibitor anginex, and that the protein is crucial for tumor angiogenesis. gal-1 is overexpressed in endothelial cells of different human tumors. Expression knockdown in cultured endothelial cells inhibits cell proliferation and migration. The importance of gal-1 in angiogenesis is illustrated in the zebrafish model, where expression knockdown results in impaired vascular guidance and growth of dysfunctional vessels. The role of gal-1 in tumor angiogenesis is demonstrated in gal-1-null mice, in which tumor growth is markedly impaired because of insufficient tumor angiogenesis. Furthermore, tumor growth in gal-1-null mice no longer responds to antiangiogenesis treatment by anginex. Thus, gal-1 regulates tumor angiogenesis and is a target for angiostatic cancer therapy.

Animals↗
PubMed2006

Angiogenesis-independent tumor growth mediated by stem-like cancer cells.

In this work, highly infiltrative brain tumors with a stem-like phenotype were established by xenotransplantation of human brain tumors in immunodeficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells expressed neural stem cell markers, showed a migratory behavior similar to normal human neural stem cells, and gave rise to tumors in vivo after regrafting. Serial passages in animals gradually transformed the tumors into an angiogenesis-dependent phenotype. This process was characterized by a reduction in stem cells markers. Gene expression profiling combined with high throughput immunoblotting analyses of the angiogenic and nonangiogenic tumors identified distinct signaling networks in the two phenotypes. Furthermore, proinvasive genes were up-regulated and angiogenesis signaling genes were down-regulated in the stem-like tumors. In contrast, proinvasive genes were down-regulated in the angiogenesis-dependent tumors derived from the stem-like tumors. The described angiogenesis-independent tumor growth and the uncoupling of invasion and angiogenesis, represented by the stem-like cancer cells and the cells derived from them, respectively, point at two completely independent mechanisms that drive tumor progression. This article underlines the need for developing therapies that specifically target the stem-like cell pools in tumors.

Animals↗
PubMed2002

Orchestration of angiogenesis and arteriovenous contribution by angiopoietins and vascular endothelial growth factor (VEGF).

Multiple classes of factors contribute to angiogenesis. In past years, the primary focus has been to understand the functions of individual classes of angiogenic factors. However, few studies have focused on the combinatorial roles of multiple classes of factors in angiogenesis. In this report, we have investigated the in vivo angiogenic processes regulated by two major classes of angiogenic factors, the angiopoietins and vascular endothelial growth factor (VEGF). Here we show that angiopoietin-1, a factor previously considered to be proangiogenic, can offset VEGF-induced angiogenesis in vivo. We also provide direct in vivo evidence for the synergistic effect of angiopoietin-2 and VEGF on the induction of angiogenesis. Furthermore, we show that these two classes of factors control the ratio of arterial and venous blood vessel types during angiogenesis. We believe that our study is a step toward understanding how multiple classes of factors harmonize angiogenesis and blood vessel types.

Angiopoietin-1↗
PubMed2005

A synthetic glycosaminoglycan mimetic binds vascular endothelial growth factor and modulates angiogenesis.

In a previous study, we showed that in situ injection of glycosaminoglycan mimetics called RGTAs (ReGeneraTing Agents) enhanced neovascularization after skeletal muscular ischemia (Desgranges, P., Barbaud, C., Caruelle, J. P., Barritault, D., and Gautron, J. (1999) FASEB J. 13, 761-766). In the present study, we showed that the RGTA OTR4120 modulated angiogenesis in the chicken embryo chorioallantoic membrane assay, in a dose-dependent manner. We therefore investigated the effect of OTR4120 on one of the most specific angiogenesis-regulating heparin-binding growth factors, vascular endothelial growth factor 165 (VEGF165). OTR4120 showed high affinity binding to VEGF165 (Kd = 2.2 nm), as compared with heparin (Kd = 15 nm), and potentiated the affinity of VEGF165 for VEGF receptor-1 and -2 and for neuropilin-1. In vitro, OTR4120 potentiated VEGF165-induced proliferation and migration of human umbilical vein endothelial cells. In the in vivo Matrigel plug angiogenesis assay, OTR4120 in a concentration as low as 3 ng/ml caused a 6-fold increase in VEGF165-induced angiogenesis. Immunohistochemical staining showed a larger number of well differentiated VEGFR-2-expressing-cells in Matrigel sections of OTR4120-treated plug than in control sections. These findings indicate that OTR4120 enhances the VEGF165-induced angiogenesis and therefore may hold promise for treating disorders characterized by deficient angiogenesis.

Animals↗
PubMed2006

Divergent effects of quercetin conjugates on angiogenesis.

The present study reports the activities of quercetin and its main circulating conjugates in man (quercetin-3'-sulphate (Q3'S) and quercetin-3-glucuronide (Q3G)) on in vivo angiogenesis induced by vascular endothelial growth factor (VEGF) and examines the effects of these molecules on cultured endothelial cells. We found opposing effects of quercetin and its metabolites on angiogenesis. While quercetin and Q3G inhibited VEGF-induced endothelial cell functions and angiogenesis, Q3'S per se promoted endothelial cell proliferation and angiogenesis. The inhibitory effect elicited by Q3G was linked to inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation elicited by VEGF. The activation of endothelial cells by Q3'S was associated to stimulation of VEGF receptor-2 and to downstream signalling activation (phosphatidylinositol-3 kinase/Akt and nitric oxide synthase pathways), ultimately responsible for ERK1/2 phosphorylation. These data indicate that the effects of circulating quercetin conjugates on angiogenesis are different depending on the nature of the conjugate. Q3G and Q3'S are the two major conjugates in plasma, but their ratio is dependent on several factors, so that inhibition or activation of angiogenesis could be subtly shifted as a result of metabolism in vivo.

Animals↗
PubMed2005

Toxicological screening for the effects of short-term exposure of sidestream cigarette smoke on angiogenesis.

Angiogenesis is a fundamental process that ensures adequate metabolic supply to tissues in numerous biological and pathological states, including tumorigenesis. Cigarette smoking causes numerous adverse effects, some of which are associated with disruption of the normal process of angiogenesis. It is believed that sidestream cigarette smoke severely affects different components that help in the normal process of angiogenesis. Sidestream cigarette smoke is composed primarily of smoke that emanates from the burning end of a cigarette, and contaminants that diffuse through the cigarette paper. The aim of the current study was to ascertain the toxicological effects of different sidestream cigarette smoke solutions (SSCSS) on angiogenesis by using chicken chorioallantoic membrane (CAM) assay. Decrease in total vascular area, diameter of secondary and tertiary blood vessels, cell proliferation, migration of blood vessels toward ectoderm, and number of capillary plexuses formation was observed by application of SSCSS. Scanning microscopy also revealed deviation in pattern formed by the major capillary plexuses and the fibrillar elements of the mesoderm SSCSS in treated CAMs. It is concluded that SSCSS may hinder the normal process of angiogenesis resulting in abnormal blood supply to tissues and decreased repair and remodeling, which are common problems among smoke-exposed individuals. Further study is required to delineate the effects of different chemicals in SSCSS on angiogenesis.

Animals↗
PubMed2004

Antioxidants inhibit angiogenesis in vivo through down-regulation of nitric oxide synthase expression and activity.

Although reactive oxygen species (ROS) participate in many cellular mechanisms, only few data exist concerning their involvement in physiological angiogenesis. The aim of the present work was to elucidate possible mechanisms through which ROS affect angiogenesis in vivo, using the model of the chicken embryo chorioallantoic membrane (CAM). Superoxide dismutase (SOD) and its membrane permeable mimetic tempol, dose dependently decreased angiogenesis and down-regulated inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. The NADPH oxidase inhibitors, 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF) and apocynin, but not allopurinol, also had a dose dependent inhibitory effect on angiogenesis and NO production in vivo. Catalase and the intracellular hydrogen peroxide (H2O2) scavenger sodium pyruvate decreased, while H2O2 increased in a dose-dependent manner the number of CAM blood vessels, as well as the expression and activity of iNOS. Dexamethasone, which down-regulated NO production by iNOS and L-NAME, but not D-NAME, dose dependently decreased angiogenesis in vivo. These data suggest that antioxidants affect physiological angiogenesis in vivo, through regulation of NOS expression and activity.

Allantois↗
PubMed2002

Defective angiogenesis in the inflammatory granulation tissue in histidine decarboxylase-deficient mice but not in mast cell-deficient mice.

We have analyzed the role of histamine in the angiogenesis of the granulation tissue in histidine decarboxylase-deficient (HDC(-/-)) mice, mast cell-deficient mice (WBB6F1-W/W(V)), and their corresponding wild-type mice (HDC(+/+) and WBB6F(1)(+/+)). In HDC(+/+) mice, subcutaneous implantation of a cotton thread in the dorsum induced granulation tissue formation with angiogenesis, while the topical injection of anti-vascular endothelial growth factor (VEGF) IgG strongly suppressed them. In HDC(-/-) mice which showed lower VEGF levels in the granulation tissue, there was notably less angiogenesis and granulation tissue formation than in HDC(+/+) mice. The topical injection of histamine or the H(2) agonist dimaprit rescued the defective angiogenesis and granulation tissue formation in HDC(-/-) mice. There was no significant difference in the granulation tissue formation and angiogenesis between WBB6F1-W/W(V) and WBB6F1(+/+) mice. In addition, macrophages in the granulation tissue were found to express HDC. Our findings indicate that histamine derived from non-mast cells plays a significant role in the angiogenesis of the inflammatory granulation tissue.

Animals↗
PubMed2002

Active immunization against the vascular endothelial growth factor receptor flk1 inhibits tumor angiogenesis and metastasis.

The vascular endothelial growth factor (VEGF) receptor fetal liver kinase 1 (flk1; VEGFR-2, KDR) is an endothelial cell-specific receptor tyrosine kinase that mediates physiological and pathological angiogenesis. We hypothesized that an active immunotherapy approach targeting flk1 may inhibit tumor angiogenesis and metastasis. To test this hypothesis, we first evaluated whether immune responses to flk1 could be elicited in mice by immunization with dendritic cells pulsed with a soluble flk1 protein (DC-flk1). This immunization generated flk1-specific neutralizing antibody and CD8+ cytotoxic T cell responses, breaking tolerance to self-flk1 antigen. Tumor-induced angiogenesis was suppressed in immunized mice as measured in an alginate bead assay. Development of pulmonary metastases was strongly inhibited in DC-flk1-immunized mice challenged with B16 melanoma or Lewis lung carcinoma cells. DC-flk1 immunization also significantly prolonged the survival of mice challenged with Lewis lung tumors. Thus, an active immunization strategy that targets an angiogenesis-related antigen on endothelium can inhibit angiogenesis and may be a useful approach for treating angiogenesis-related diseases.

Animals↗