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PubMedDate not supplied

Role of alpha(v) integrins and angiogenesis during wound repair.

Angiogenesis, the formation of new blood vessels from pre-existing blood vessels, is thought to be critical for wound repair. Yet few studies have critically examined dermal wound repair in a system in which angiogenesis was impaired. Since alpha(v)-containing integrins are critical for angiogenesis, we administered either an alpha(v) integrin blocking antibody or cyclic Arg-Gly-Asp peptide into a murine excisional wound model to restrict wound angiogenesis. Although both methods markedly decreased wound angiogenesis, decreased angiogenesis had no significant effect on wound epithelization, contraction, or ultimate wound closure. These results suggest that if other cellular components of wound healing are intact, moderate impairment of angiogenesis alone does not necessarily retard normal wound healing.

Animals↗
PubMed2001

Angiogenesis during implantation, and placental and early embryonic development.

Angiogenesis, the development of new capillaries from pre-existing vessels, is induced by inflammation, wound healing, immune reactions and neoplasia, and is required for tumour growth and progression. Angiogenesis participates in a wide range of ovulatory-related and non-ovulatory-related reproductive processes. We present a review of current data pertaining to angiogenesis of pregnancy, with specific emphasis on implantation and placental and embryonic development in both normal physiology processes and various pathological conditions. To this goal, MEDLINE, Current Contents and Index Medicus were searched for studies published between 1966 and August 1999. Pertinent studies (including human and animal models) pertaining to angiogenesis of implantation and placental and embryonic development were reviewed. Current literature supports that angiogenesis is an essential physiological component of implantation, and placental and embryonic development. Angiogenesis also actively participates in abnormal implantation, and various pathological processes of the placenta including those observed in association with pre-eclampsia, growth restriction, maternal anaemia in the first-trimester and other hypoxia-related conditions during pregnancy. Finally, administration of an angiogenesis inhibitor (AGM-1470) in mice has been shown to result in complete failure of embryonic growth due to interference with decidualization, placental and yolk sac formation, and embryonic vascular development.

Adult↗
PubMed2001

Magnetic resonance imaging applications in the evaluation of tumor angiogenesis.

Angiogenesis, the growth of new blood vessels, is a critical component in the development of solid tumors. Over the last decade, progress in the study of the biology of angiogenesis has led to identification of a large number of molecules that promote, participate, and regulate the growth of new vessels in normal tissue and in tumors. Consequently, many new targets for suppression of angiogenesis have been identified and are now at various stages of development and evaluation in clinical trials. Magnetic resonance imaging (MRI) provides an attractive tool for in vivo analysis of the basic biology of angiogenesis, for preclinical evaluation of the activity of a number of potential antiangiogenic agents, as well as for clinical detection, diagnosis, and prognosis. One of the features of MRI is the wide range of physiologic parameters by which angiogenesis can be imaged. This review presents the biological basis of angiogenesis with emphasis on characteristics of the neovasculature that can be used for imaging, followed by an overview of the MRI approaches that are being evaluated for the analysis of tumor angiogenesis.

Blood Volume↗
PubMed2002

In vitro and in vivo angiogenesis in PC12 pheochromocytoma cells is mediated by vascular endothelial growth factor.

Angiogenesis, the formation of new blood vessels from existing vascular endothelium, is essential for tumor growth. Vascular endothelial growth factor (VEGF) is an endotheliumspecific mitogen and regulator of angiogenesis. Angiogenesis has been associated to the malignant phenotype of pheochromocytomas and is readily observed in experimental pheochromocytomas. Although VEGF gene expression has already been demonstrated in the rat PC12 cell line, the detailed mechanisms of action are not known. We have, therefore, studied angiogenesis in the rat PC12 pheochromocytoma cell line in vitro and in vivo. VEGF gene expression and accumulation of VEGF protein in cytoplasm and conditioned medium of PC12 cells was found. Conditioned medium from PC12 cells significantly increased proliferation of VEGF-dependent endothelial cells from human umbilical veins, and this effect reversed upon addition of a neutralizing anti-VEGF antibody. Dexamethasone and nerve growth factor (NGF) increased VEGF mRNA expression and accumulation of VEGF protein of PC12 subclones with established metastatic activity in vivo. PC12 cells xenotransplanted to nude mice had marked VEGF expression and induced host angiogenesis, confirmed by the presence of CD34-positive endothelial cells in the experimental PC12 tumors. When NGF-primed PC12 cells were immobilized in Matrigel supplemented with rising concentrations of the growth factor and xenotransplanted, increasing NGF resulted in tumors with smaller areas of necrosis and increased vital tumor volume. These results suggest that VEGF is a mediator of angiogenesis in the PC12 pheochromocytoma cell line, and that dexamethasone and NGF affect VEGF expression. Our data further suggest that NGF may contribute to angiogenesis in experimental pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed2000

Parathyroid-induced angiogenesis is VEGF-dependent.

BACKGROUND: Autotransplantation of parathyroid tissue after parathyroidectomy is successful at salvaging parathyroid function. The relatively high success of parathyroid transplantation is thought to be due, in part, to the ability of parathyroid tissue to induce angiogenesis and thus recruit a new vasculature. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor produced by a number of tumors and hypoxic tissues. Using a 3-dimensional intact microvessel angiogenesis system, we evaluated the role of VEGF in the stimulation of angiogenesis by human parathyroid cells. METHODS: Freshly isolated rat microvessels embedded in a 3-dimensional collagen I matrix were treated with healthy 1-mm(3) fragments of human parathyroid tissue or isolated parathyroid cells. Other gels were supplemented with VEGF(165) or FLT-1 soluble receptor fusion protein to bind VEGF. After 11 days in culture, the gels were stained with Gs-1 lectin, a marker for rat endothelium, and linear growth of the microvessels was determined by using image analysis. Parathyroid production of VEGF was determined with reverse transcriptase-polymerase chain reaction. RESULTS: A significant increase in microvessel growth was seen in parathyroid coculture (8.4 +/- 1.0 mm) versus VEGF(165) supplemented gels (6.2 +/- 0.3 mm, P <.01). VEGF(165) significantly augmented parathyroid-stimulated angiogenesis (13.7 +/- 2.4 mm, P <.05 vs parathyroid alone). Using quantitative reverse transcriptase-polymerase chain reaction, we identified VEGF messenger RNA (mRNA) induction within 1 hour of parathyroid explant, with a 12-fold increase by 24 hours. Treatment of parathyroid cocultures with 0.2 microg/mL FLT-1 soluble receptor protein completely eliminated the parathyroid induction of angiogenesis. CONCLUSIONS: Parathyroid tissue expresses low levels of VEGF mRNA, which is significantly upregulated on explantation. Furthermore, the increased VEGF expression is essential to drive parathyroid-induced angiogenesis in our model. However, our data suggests that other parathyroid-produced factors are involved in mediating parathyroid-induced angiogenesis.

Adipose Tissue↗
PubMed2000

Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells.

Phosphatidylinositol 3-kinase (PI 3-kinase) is a signaling molecule that controls numerous cellular properties and activities. The oncogene v-p3k is a homolog of the gene coding for the catalytic subunit of PI 3-kinase, p110alpha. P3k induces transformation of cells in culture, formation of hemangiosarcomas in young chickens, and myogenic differentiation in myoblasts. Here, we describe a role of PI 3-kinase in angiogenesis. Overexpression of the v-P3k protein or of cellular PI 3-kinase equipped with a myristylation signal, Myr-P3k, can induce angiogenesis in the chorioallantoic membrane (CAM) of the chicken embryo. This process is characterized by extensive sprouting of new blood vessels and enlargement of preexisting vessels. Overexpression of the myristylated form of the PI 3-kinase target Akt, Myr-Akt, also induces angiogenesis. Overexpression of the tumor suppressor PTEN or of dominant-negative constructs of PI 3-kinase inhibits angiogenesis in the yolk sac of chicken embryos, suggesting that PI 3-kinase and Akt signaling is required for normal embryonal angiogenesis. The levels of mRNA for vascular endothelial growth factor (VEGF) are elevated in cells expressing activated PI 3-kinase or Myr-Akt. VEGF mRNA levels are also increased by insulin treatment through the PI 3-kinase-dependent pathway. VEGF mRNA levels are decreased in cells treated with the PI 3-kinase inhibitor LY294002 and restored by overexpression of v-P3k or Myr-Akt. Overexpression of VEGF by the RCAS vector induces angiogenesis in chicken embryos. These results suggest that PI 3-kinase plays an important role in angiogenesis and regulates VEGF expression.

Animals↗
PubMed2005

Preventing local regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 enhances angiogenesis.

Angiogenesis restores blood flow to healing tissues, a process that is inhibited by high doses of glucocorticoids. However, the role of endogenous glucocorticoids and the potential for antiglucocorticoid therapy to enhance angiogenesis is unknown. Using in vitro and in vivo models of angiogenesis in mice, we examined effects of (i) endogenous glucocorticoids, (ii) blocking endogenous glucocorticoid action with the glucocorticoid receptor antagonist RU38486, and (iii) abolishing local regeneration of glucocorticoids by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1). Glucocorticoids, administered at physiological concentrations, inhibited angiogenesis in an in vitro aortic ring model and in vivo in polyurethane sponges implanted s.c. RU38486-enhanced angiogenesis in s.c. sponges, in healing surgical wounds, and in the myocardium of mice 7 days after myocardial infarction induced by coronary artery ligation. 11betaHSD1 knockout mice showed enhanced angiogenesis in vitro and in vivo within sponges, wounds, and infarcted myocardium. Endogenous glucocorticoids, including those generated locally by 11betaHSD1, exert tonic inhibition of angiogenesis. Inhibition of 11betaHSD1 in liver and adipose has been advocated to reduce cardiovascular risk in the metabolic syndrome: these data suggest that 11betaHSD1 inhibition offers a previously uncharacterized therapeutic approach to improve healing of ischemic or injured tissue.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2001

Whole-body and intravital optical imaging of angiogenesis in orthotopically implanted tumors.

The development of drugs for the control of tumor angiogenesis requires a simple, accurate, and economical assay for tumor-induced vascularization. We have adapted the orthotopic implantation model to angiogenesis measurement by using human tumors labeled with Aequorea victoria green fluorescent protein for grafting into nude mice. The nonluminous induced capillaries are clearly visible against the very bright tumor fluorescence examined either intravitally or by whole-body luminance in real time. The orthotopic implantation model of human cancer has been well characterized, and fluorescence shadowing replaces the laborious histological techniques for determining blood vessel density. Intravital images of orthotopically implanted human pancreatic tumors clearly show angiogenic capillaries at both primary and metastatic sites. A quantitative time course of angiogenesis was determined for an orthotopically growing human prostate tumor periodically imaged intravitally in a single nude mouse over a 19-day period. Whole-body optical imaging of tumor angiogenesis was demonstrated by injecting fluorescent Lewis lung carcinoma cells into the s.c. site of the footpad of nude mice. The footpad is relatively transparent, with comparatively few resident blood vessels, allowing quantitative imaging of tumor angiogenesis in the intact animal. Capillary density increased linearly over a 10-day period as determined by whole-body imaging. Similarly, the green fluorescent protein-expressing human breast tumor MDA-MB-435 was orthotopically transplanted to the mouse fat pad, where whole-body optical imaging showed that blood vessel density increased linearly over a 20-week period. These powerful and clinically relevant angiogenesis mouse models can be used for real-time in vivo evaluation of agents inhibiting or promoting tumor angiogenesis in physiological microenvironments.

Animals↗
PubMed2000

Chymase as a proangiogenic factor. A possible involvement of chymase-angiotensin-dependent pathway in the hamster sponge angiogenesis model.

We investigated the profound involvement of chymase, an alternative angiotensin II-generating enzyme, in angiogenesis using a hamster sponge implant model. In vivo transfection of human pro-chymase cDNA or a direct injection of purified chymase into the sponges implanted resulted in marked increment of hemoglobin contents in the sponge granuloma tissues, demonstrating that chymase has an ability to elicit angiogenesis and is a potent angiogenic factor. Daily injection of basic fibroblast growth factor into the sponges implanted also induced angiogenesis, which was suppressed by the treatment with chymostatin, an inhibitor of chymase, or TCV-116, an antagonist of angiotensin II (Ang II) type 1 receptor. Expression of chymase mRNA and production of Ang II in the granuloma tissues were enhanced by the stimulation with basic fibroblast growth factor. Chymase activity in the sponge granulomas increased in parallel with the rise in hemoglobin contents, and mast cells observed in the granuloma tissues were positively stained with anti-chymase antibody. Exogenous administration not only of Ang II but of angiotensin I (Ang I) directly into the sponges could enhance angiogenesis. Chymostatin inhibited the angiogenesis induced by Ang I but not Ang II, suggesting the presence of a chymase-like Ang II-generating activity in the sponge granulomas. Our results may suggest a potential ability of chymase to promote angiogenesis through the local chymase-dependent and angiotensin-converting enzyme-dependent Ang II generating system in pathophysiological angiogenesis.

Angiotensin I↗
PubMed2003

Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth.

Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild-type (WT) mice formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase (COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3(-/-)) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3(-/-), in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3(-/-), compared with WT. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3(-/-). These results demonstrate significance of host stromal PGE(2)-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors.

Animals↗
PubMed2005

Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth.

Angiotensin II is a multi-functional bioactive peptide and recent reports have suggested that angiotensin II is a proangiogenic growth factor. A retrospective cohort study revealed that angiotensin converting enzyme inhibitors decreased cancer risk, however, the precise mechanism is unknown. We hypothesized that endogenous angiotensin II plays a crucial role in tumor-associated angiogenesis. Tumors implanted in the subcutaneous tissue of wild-type mice developed intensive angiogenesis with vascular endothelial growth factor (VEGF) induction in tumor stroma. AT1a receptor (AT1a-R), but not AT1b receptor or AT2 receptor was expressed in tumor stroma and systemic administration of an AT1-R antagonist reduced tumor-associated angiogenesis and VEGF expression in tumor stroma. Angiotensin II up-regulates VEGF expression through the pathway including protein kinase C, AP-1 and NF-kappaB in fibroblasts, the major cellular component of tumor stroma. VEGF is a major determinant of tumor-associated angiogenesis in the present model, since angiogenesis was markedly reduced by either a VEGF neutralizing antibody or a VEGF receptor kinase inhibitor. Compared with the wild-type, tumor-associated angiogenesis was reduced in AT1a-R null mice, with reduced expression of VEGF in the stroma, and this reduction in AT1a-R null mice was not inhibited by an AT1-R antagonist. These suggest that host stromal VEGF induction by AT1a-R signaling is a key regulator of tumor-associated angiogenesis and tumor growth. AT1a-R signaling blockade may be a novel and effective therapeutic strategy against cancers.

Angiotensin II↗
PubMed2006

1alpha, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis.

Angiogenesis is an essential step in initial tumor development and metastasis. Consequently, compounds that inhibit angiogenesis would be useful in treating cancer. A variety of antitumor effects mediated by 1alpha, 25-dihydroxyvitamin D3 (1,25-VD) have been reported, one of which is anti-angiogenesis; however, detailed mechanisms remain unclear. We have demonstrated that 1,25-VD inhibits prostate cancer (PCa) cell-induced human umbilical vein endothelial cell migration and tube formation, two critical steps involved in the angiogenesis. An angiogenesis factor, interleukin-8 (IL-8), secreted from PCa cell was suppressed by 1,25-VD at both mRNA and protein levels. Mechanistic dissection found that 1,25-VD inhibits NF-kappaB signal, one of the most important IL-8 upstream regulators. The 1,25-VD-mediated NF-kappaB signal reduction was shown to result from the blocking of nuclear translocation of p65, a subunit of the NF-kappaB complex, and was followed by attenuation of the NF-kappaB complex binding to DNA. The role of IL-8 in PCa progression was further examined by PCa tissue microarray analyses. We found that IL-8 expression was elevated during PCa progression, which suggests that IL-8 may play a role in tumor progression mediated through its stimulation on angiogenesis. These findings indicate that 1,25-VD could prevent PCa progression by interrupting IL-8 signaling, which is required in tumor angiogenesis, and thus applying vitamin D in PCa treatment may be beneficial for controlling disease progression.

Calcitriol↗
PubMed1990

Effect of host age on tumor-associated angiogenesis in mice.

Previous reports on the slower growth of tumors in senescent mice have suggested a decrease in tumor angiogenesis in these animals, but such an observation has not yet been documented quantitatively. In this study, we report the relative amount of tumor angiogenesis and tumor volume for two different types of tumor in 11 young (8-9-wk old) versus nine older (19-mo old) male C57BL/10 mice. B16 melanoma or SP1 methylcholanthrene-induced fibrosarcoma cells were injected into the ventral skin of mice. After 3 days, the mice were killed and the injection sites were examined for angiogenesis surrounding the tumor (centrally directed tumor angiogenesis), nerve-associated angiogenesis, and tumor volume. In the older mice, there was significantly less centrally directed tumor angiogenesis for both tumors tested, and nerve-associated angiogenesis was decreased for B16 melanoma. The mean tumor volume for the B16 implants was smaller for the older animals, but the mean SP1 tumor volumes were identical for both age groups. These findings support the hypothesis that tumor growth in older animals is associated with less formation of new blood vessels, and this may explain the slower tumor growth observed in aged animals with certain experimental tumors.

Aging↗
PubMed2004

Serum response factor is a critical requirement for VEGF signaling in endothelial cells and VEGF-induced angiogenesis.

Angiogenesis, new capillary blood vessel formation, is essential for embryonic development, wound healing, and cancer growth. Vascular endothelial growth factor (VEGF) induces angiogenesis by activating endothelial cell migration and proliferation. Serum response factor (SRF) is a transcription factor important for embryonic development and activation of immediate early gene expression. The roles of SRF in endothelial cell biology and angiogenesis have not been explored. Here we demonstrate that SRF is a downstream mediator of VEGF signaling in endothelial cells and a critical requirement for VEGF-induced angiogenesis. Knockdown of SRF protein levels in human and rat endothelial cells abolished VEGF-induced in vitro angiogenesis, impaired endothelial cell migration and proliferation, and inhibited VEGF-induced actin polymerization and immediate early gene expression. Injection of SRF antisense expression plasmid into gastric ulcers in rats significantly inhibited in vivo angiogenesis in granulation tissue. Mechanistically, this study also revealed that VEGF promotes SRF expression and nuclear translocation and increases SRF binding activity to DNA in endothelial cells through both Rho-actin and MEK-ERK dependent signaling pathways. These findings have potential therapeutic implications, e.g., local anti-SRF treatment may inhibit angiogenesis crucial for tumor growth.

Acetic Acid↗
PubMed1995

Tumor angiogenesis as a predictor of recurrence and survival in patients with node-negative colon cancer.

OBJECTIVE: The authors' objective was to quantitatively assess angiogenesis or neovascularity within node-negative colon cancers and to determine if increased angiogenesis correlated with higher recurrence and lower survival rates. SUMMARY BACKGROUND DATA: Neovascularization promotes rapid tumor growth by facilitating nutrient and metabolite exchange. Recent work with breast and nonsmall cell lung cancers has shown that low angiogenic activity imparts a lower risk of recurrence and metastasis. Although adjuvant therapy is beneficial for patients with node-positive colon cancers, no such benefit has been demonstrated for patients with node-negative lesions. Nevertheless, up to 30% of this latter group will experience recurrence. We sought to identify a subset of patients with node-negative colon cancers at high risk for recurrence who might benefit from such therapy. METHODS: One hundred five node-negative colon cancers were immunostained for endothelial cell factor VIII-related antigen. Blood vessels within three microscopic fields at 100X magnification were counted, the mean calculated, and an angiogenesis score assigned. A subjective angiogenesis grade (1-4) was assigned after each slide was surveyed in its entirety. Score and grade were then assessed with respect to cancer recurrence and patient survival. RESULTS: Mean patient age was 71 years (range, 41-90 years) and mean tumor size, 5.6 cm (range, 2-12 cm). Mean follow-up was 6.5 years; mean angiogenesis score, 27.9 (range, 4-50); and mean grade, 2.0 (range, 1-4). Patients living 5 years had significantly lower angiogenesis scores than did nonsurvivors (22.8 vs. 43.2, p = 0.0004). Each 10-vessel increase in score imparted a 2.0-fold greater hazard of death and a 2.7-fold greater hazard of recurrence. The probability of surviving 5 years is estimated by: [formula: see text] and the probability of recurrence is estimated by: [formula: see text] CONCLUSIONS: Angiogenesis within colon cancer is an important predictor of tumor behavior and may identify patients at higher risk for recurrence and early death.

Adenocarcinoma↗
PubMed1992

Effect of 15-deoxyspergualin, a microbial angiogenesis inhibitor, on the biological activities of bovine vascular endothelial cells.

We found recently that 15-deoxyspergualin, an analog of spergualin, which is an antibiotic and includes a spermidine moiety in its structure, exhibits anti-angiogenic activity. We have now carried out in vitro experiments with bovine vascular endothelial cells to determine which events occurring during angiogenesis are affected by this microbial angiogenesis inhibitor. 15-Deoxyspergualin did not inhibit the production of urokinase-type plasminogen activator (u-PA) or type IV collagenase by vascular endothelial cells. The direct inhibition of u-PA activity by 15-deoxyspergualin was not observed either. The angiostatic antibiotic neither affected the migration of vascular endothelial cells nor inhibited the endothelial cell proliferation in a two-dimensional culture system. We also examined the effect of 15-deoxyspergualin on the proliferation of endothelial cells in a three-dimensional culture system involving collagen gel, in which cell growth resembles more closely the endothelial cell proliferation during in vivo angiogenesis than that in a two-dimensional culture system without collagen gel. The antibiotic inhibited cell proliferation in a dose-dependent manner, indicating that the three-dimensional culture system is useful for finding a new angiogenesis inhibitor with a different mode of action from those of angiogenesis inhibitors found by using a two-dimensional assay system; however, no cause-effect relationship has yet been established. Taken together, these results suggest the possible involvement of the inhibition of vascular endothelial cell growth by 15-deoxyspergualin in its angiogenesis-inhibitory effect. 15-Deoxyspergualin appears to be a promising candidate as an angiogenesis inhibitor for controlling aberrant angiogenic responses occurring in different states, including tumor development.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Retroviral delivery of homeobox D3 gene induces cerebral angiogenesis in mice.

Angiogenesis is regulated by concerted actions of angiogenic and angiostatic factors. Homeobox D3 gene (HOXD3) is a potent proangiogenic transcription factor that promotes angiogenesis by modulating the expression of matrix-degrading proteinases, integrins, and extracellular matrix components. Application of HOXD3 can promote angiogenesis in the skin, but its role in other vascular beds has not been examined. The authors examined HOXD3 expression in human brain vessels by in situ hybridization. Although little or no HOXD3 mRNA was detected in normal brain vessels, increased levels of HOXD3 and its target gene, alpha V beta 3, were found in angiogenic vessels in human brain arteriovenous malformations. The authors further investigated whether HOXD3 plays a role in cerebral angiogenesis in a murine model. Expression of HOXD3 in mouse brain was achieved through retroviral vector-mediated HOXD3 gene transfer. HOXD3 expression lead to a significant induction of cerebral angiogenesis as shown by quantitative microvessel counting (HOXD3: 241 +/- 19 vessels/mm2 vs. saline: 150 +/- 14 vessels/mm2, P < 0.05). The data also showed that focal cerebral blood flow was increased in the angiogenic region with less vascular leakage. Moreover, expression of HOXD3 led to an increase in the expression of a direct downstream target gene alpha V beta 3 integrin. The data suggest that HOXD3 may play an important role in regulating cerebral angiogenesis, and that gene transfer of HOXD3 may provide a novel and potent means to stimulate angiogenesis.

Animals↗
PubMed1996

Interleukin-12 inhibits angiogenesis induced by human tumor cell lines in vivo.

Tumor cell-induced angiogenesis, i.e., new blood vessel formation within tumor tissue, is an essential requirement for the growth of solid neoplasms. Interleukin-12 (IL-12) inhibits growth of a variety of experimental tumors in vivo. We tested whether antitumor activity of IL-12 is related to the inhibition of angiogenesis induced by tumor cell lines. Angiogenesis was induced in x-ray immunosuppressed Balb/c mice by intradermal injection of the following human tumor cells: T47D, originating from mammary carcinoma; A431, derived from vulval carcinoma; and Skv, established from bowenoid papulosis, Systemic treatment of the mice with murine IL-12 significantly decreased angiogenesis induced by human tumor cells in a time-and dose-dependent manner. Preincubation of human cells in vitro with IL-12 did not inhibit tumor cell-induced angiogenesis, suggesting that the antiangiogenic capacity of IL-12 is restricted to in vivo conditions. Treatment of the mice with rat antibody against murine interferon-gamma (IFN-gamma) resulted in counteracting the antiangiogenic effect of murine IL-12. Furthermore, human IFN-gamma inhibited the angiogenic activity of human tumor cell lines. This indicates that IFN-gamma is a mediator of the antiangiogenic effect of IL-12. The results show that the mechanism of antitumor action of IL-12 may depend not only on the immunostimulatory activity of this cytokine but also on its effect on tumor cell-induced angiogenesis. IL-12 should be considered as a potential candidate for the treatment of angiogenesis-dependent malignancies.

Animals↗