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PubMed2006

Inhibition of angiogenesis by vitamin D-binding protein: characterization of anti-endothelial activity of DBP-maf.

Angiogenesis is a complex process involving coordinated steps of endothelial cell activation, proliferation, migration, tube formation and capillary sprouting with participation of intracellular signaling pathways. Regulation of angiogenesis carries tremendous potential for cancer therapy. Our earlier studies showed that vitamin D-binding protein-macrophage activating factor (DBP-maf) acts as a potent anti-angiogenic factor and inhibits tumor growth in vivo. The goal of this investigation was to understand the effect of DBP-maf on human endothelial cell (HEC) and the mechanism of angiogenesis inhibition. DBP-maf inhibited human endothelial cell (HEC) proliferation by inhibiting DNA synthesis (IC(50) = 7.8 +/- 0.15 microg/ml). DBP-maf significantly induced S- and G0/G1-phase arrest in HEC in 72 h. DBP-maf potently blocked VEGF-induced migration, tube-formation of HEC in a dose dependent manner. In addition, DBP-maf inhibited growth factor-induced microvessel sprouting in rat aortic ring assay. Moreover, DBP-maf inhibited VEGF signaling by decreasing VEGF-mediated phosphorylation of VEGFR-2 and ERK1/2, a downstream target of VEGF signaling cascade. However, Akt activation was not affected. These studies collectively demonstrate that DBP-maf inhibits angiogenesis by blocking critical steps such as HEC proliferation, migration, tube formation and microvessel sprouting. DBP-maf exerts its effect by inhibiting VEGR-2 and ERK1/2 signaling cascades. Understanding the cellular and molecular mechanisms of anti-endothelial activity of DBP-maf will allow us to develop it as an angiogenesis targeting novel drug for tumor therapy.

Cell Migration Inhibition↗
PubMed2006

MT1-MMP: universal or particular player in angiogenesis?

Tumorigenesis involves not only tumor cells that become transformed but also the peritumoral stroma which reacts inducing inflammatory and angiogenic responses. Angiogenesis, the formation of new capillaries from preexisting vessels, is an absolute requirement for tumor growth and metastasis, and it can be induced and modulated by a wide variety of soluble factors. During angiogenesis, quiescent endothelial cells are activated and they initiate migration by degrading the basement membranes through the action of specific proteases, in particular of matrix metalloproteinases (MMPs). Among these, the membrane type 1-matrix metalloproteinase (MT1-MMP) has been identified as a key player during the angiogenic response. In this review, we will summarize the role of MT1-MMP in angiogenesis and the regulatory mechanisms of this protease in endothelial cells. Since our recent findings have suggested that MT1-MMP is not universally required for angiogenesis, we hypothesize that the regulation and participation of MT1-MMP in angiogenesis may depend on the nature of the angiogenic stimulus. Experiments aimed at testing this hypothesis have shown that similarly to the chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12, lipopolysaccharide (LPS) seems to induce the formation of capillary tubes by human or mouse endothelial cells (ECs) in an MT1-MMP-independent manner. The implications of these findings in the potential use of MT1-MMP inhibitors in cancer therapy are discussed.

Animals↗
PubMed2000

Gene therapy for myocardial angiogenesis: has it come of age?

Vasculogenesis and angiogenesis are the processes responsible for the development of the circulatory system during embryonic and adult life. Vasculogenesis occurs during embryogenesis while angiogenesis refers to blood vessel formation from any preexisting vasculature. Postnatal angiogenesis resumes during reproduction, wound healing, and ischemia. Excess blood vessel formation may contribute to initiating and maintaining many diseases such as chronic inflammatory disorders, tumor growth, restenosis, and atherosclerosis. In contrast. insufficient blood vessel formation is responsible for tissue ischemia, as in coronary artery disease. An increasing number of patients with advanced coronary artery disease remain symptomatic despite maximal interventional, surgical or medical treatment. Ideally, they would benefit most from additional arterial blood supply to ischemic areas of myocardium. Therapeutic angiogenesis, the ability to induce the growth of new blood vessels, is one of the most intriguing new frontiers in interventional cardiology for this growing patient group. Several approaches are currently undergoing intensive experimental investigations or have already entered early clinical trials involving either local angiogenic peptide administration or the transfection of angiogenic genes. Gene therapy for therapeutic myocardial angiogenesis is the most promising synthesis of two emerging technologies. In the following article, we will review the fundamental pathophysiological concepts of gene-based angiogenic therapy, the technical approaches and delivery systems, and the results of the first clinical trials. We will also discuss the controversies and unresolved issues of this new revascularization therapy.

Coronary Artery Disease↗
PubMed2000

New concepts in fibrinolysis and angiogenesis.

Angiogenesis, the process by which new blood vessels form from preexisting vasculature, underlies a number of biologic processes including embryologic development, inflammation, wound healing, hypoxic retinal vascular proliferation, tumor growth, and atherosclerosis. The fibrinolytic system represents a cascade of serine protease activation events that culminate in the generation of plasmin. Although in-vitro studies suggest several possible roles that plasmin might play in angiogenesis, angiogenesis and fibrinolytic activity do not always correlate in in-vivo systems. During cutaneous and corneal wound healing, for example, angiogenesis proceeds normally in plasminogen-deficient animals. Similarly, the growth of most neoplasms is unimpaired in the absence of plasminogen. On the other hand, hypoxia-driven vascular proliferation may require plasmin-like activity, and angiogenesis within the atherosclerotic plaque seems to be associated with increased expression of fibrinolytic proteins. Recently, several nonplasmin fibrinolysins that may support the invasive phenotype of endothelial cells under specific circumstances have been identified. Thus, the contribution of individual fibrinolysins appears to be context-specific, just as the profile of endothelial cell gene expression depends upon the surrounding tissue milieu.

Animals↗
PubMed1994

Angiogenesis: an indicator of metastasis in non-small cell lung cancer invading the thoracic inlet.

We have attempted to identify a biologic rationale for the local aggressiveness and late treatment failure of resected non-small cell lung cancer involving the thoracic inlet. Tumor specimens from 28 patients who underwent a new transcervical approach were analyzed for the expression of tumor proliferative activity, suppressor-gene p53, intratumoral and peritumoral blood vessel invasion by tumor cells, the presence and degree of angiogenesis (induction of new capillaries and venules), and other biologic variables. Eighty-nine percent of the neoplasms were moderately or poorly differentiated, 89% expressed either an intermediate or high proliferative activity, 39% showed p53 aberrations, 71% exhibited induction of angiogenesis, and 39% had tumors that were positive for blood vessel invasion. With a median follow-up time of 3.5 years (range, 8 to 145+ months), the overall projected 5-year survival was 29% and the median disease-free interval was 23 months. Results of univariate and multivariate analysis of survival and the disease-free interval identified the degree of angiogenesis (density less than 1 versus more than 1 and number of neovessels less than 6 versus more than 6) as the only independent and significant predictors of the disease-free interval. Patients whose tumor showed a density of angiogenesis of 1 or greater and a number of neovessels of 6 or greater faced a significantly (p = 0.0001) higher relative risk of suffering systemic recurrence of their primary tumor than did their low-risk counterparts. Results demonstrate that angiogenesis significantly correlates with late treatment failure (metastasis), and this is acquired at a critical density and number of vessels.

Adenocarcinoma↗
PubMed1990

Induction of angiogenesis in chick yolk-sac membrane by polyamines and its inhibition by tissue inhibitors of metalloproteinases (TIMP and TIMP-2).

Treatment of yolk-sac membranes of 4-day-old chick embryos with spermine or spermidine resulted in angiogenesis in the membranes. The angiogenic activity of spermine was stronger than that of spermidine. Putrescine, polylysine and histamine did not induce angiogenesis in the membranes. Administration of putrescine, spermidine and spermine increased their respective levels in yolk-sac membranes, but no interconversion of these amines was observed. The increases in spermidine and spermine levels in yolk-sac membranes preceded induction of angiogenesis. The angiogenesis induced by spermine was inhibited by tissue inhibitors of metalloproteinases, that is, TIMP and TIMP-2. These findings suggest that spermine and spermidine are angiogenesis factors in yolk-sac membranes of chick embryos and that matrix metalloproteinases represented by collagenase are involved in their action.

Animals↗
PubMed1992

Excessive production of transforming growth-factor beta 1 can play an important role in the development of tumorigenesis by its action for angiogenesis: validity of neutralizing antibodies to block tumor growth.

Angiogenesis is an important part of tumor growth in vivo. We used the transfected Chinese hamster ovary (CHO) cells that overproduced recombinant transforming growth-factor beta 1 (TGF-beta 1) to examine the possible role of this factor in tumor growth and angiogenesis in a nude mouse model. The in-vitro proliferation of TGF-beta 1-transfected CHO cells was unaffected by the treatment of either recombinant TGF-beta 1 or an anti-TGF-beta 1 antibody. The TGF-beta 1-transfected cells grew more rapidly than the parental CHO cells when injected subcutaneously into nude mice. The tumors derived from the TGF-beta 1-transfected cells showed prominent tumor-associated angiogenesis, whereas the parental cells produced tumors without such angiogenesis. In addition, an anti-TGF-beta 1 neutralizing antibody was able to inhibit both growth and angiogenesis in the tumors derived from TGF-beta 1-transfected cells. These findings suggest that the overproduction of TGF-beta 1 by tumor cells can contribute to neovascularization and may help promote tumor development in vivo.

Animals↗
PubMed1995

Retinoids, interferon alpha, 1,25-dihydroxyvitamin D3 and their combination inhibit angiogenesis induced by non-HPV-harboring tumor cell lines. RAR alpha mediates the antiangiogenic effect of retinoids.

Retinoids combined with interferon alpha-2a (IFN alpha) or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] have shown marked synergistic inhibitory effects on angiogenesis induced by tumor cell lines harboring DNA of oncogenic human papillomaviruses (HPV) type 16 or 18. This report demonstrates comparable effects of these compounds on angiogenesis induced by non-HPV-bearing transformed cell lines, including breast carcinoma (T47D) and vulval carcinoma (A431) cell lines. Systemic treatment of mice with all-trans retinoic acid, 13-cis retinoic acid, 9-cis retinoic acid, IFN alpha or 1,25(OH)2D3 significantly decreased tumor cell-induced angiogenesis (TIA). In vitro pretreatment of T47D and A431 cells with these compounds also led to inhibition of their angiogenic capability when tested in the TIA assay. The inhibitory effects of retinoids could be counteracted by a selective antagonist of the nuclear retinoic acid receptor RAR alpha, suggesting a RAR alpha mediated mechanism of angiogenesis inhibition. The antiangiogenic effect of retinoids could be significantly enhanced by combination with IFN alpha or 1,25(OH)2D3. The results provide a further basis for the use of combinations of retinoids with IFN alpha or 1,25(OH)2D3 in the treatment of angiogenesis-dependent malignancies.

Animals↗
PubMed1995

CSF-1 treatment promotes angiogenesis in the metaphysis of osteopetrotic (toothless, tl) rats.

It has recently been shown that following treatment with colony-stimulating factor-1 (CSF-1) the osteopetrotic condition in toothless (tl) rats greatly improves and growth is accelerated. We have examined the effects of such treatment on the microvasculature of the distal femoral chondro-osseous junction, a site where bone growth in length is coordinated with angiogenesis. Vascular casts and ultrastructural analyses of this region showed that, compared to untreated normal rats, untreated mutants showed little bone growth or angiogenesis. When mutants were treated with CSF-1 angiogenesis was markedly accelerated. These data show a remarkable effect of this growth factor on angiogenesis in this osteopetrotic mutation. Whether this effect of CSF-1 on angiogenesis is direct or indirect is not known and indicates that its effects on the normal microvasculature deserve further study.

Animals↗
PubMed2006

The effects of the inhibition of inducible nitric oxide synthase on angiogenesis of epithelial ovarian cancer.

OBJECTIVE: The release of nitric oxide by tumor cells, through the stimulation of inducible nitric oxide synthase expression, may play a critical role in ovarian cancer progression. In this study we have sought to determine the effects of inhibiting inducible nitric oxide synthase on angiogenesis that was induced by 2 ovarian cancer cell lines, SKOV and MDAH2774. STUDY DESIGN: Real-time polymerase chain reaction and enzyme-linked immunosorbent assay techniques were used to determine the expression levels of inducible nitric oxide synthase and vascular endothelial growth factor in the ovarian cancer cell lines in response to treatments with L-NAME, an inhibitor of nitric oxide synthase, and SNAP, and nitric oxide donor. Ovarian cancer-induced angiogenesis was assessed in vitro with an established assay that is based on the ability of human umbilical vein endothelial cells to form a tubular network in response to angiogenic agents. RESULTS: SKOV and MDAH2774 cell lines exhibited over-expression of inducible nitric oxide synthase and have high baseline nitric oxide levels. This was associated with high levels of vascular endothelial growth factor production and angiogenesis induction. Treatment of the ovarian cancer cell lines with L-NAME significantly reduced vascular endothelial growth factor levels production and completely inhibited angiogenesis. In contrast, treatment with SNAP significantly increased vascular endothelial growth factor levels and increased angiogenesis in both cell lines. CONCLUSION: Our data suggest that the inhibition of inducible nitric oxide synthase may form a basis for a novel therapeutic treatment option for ovarian cancer therapy.

Cell Line, Tumor↗
PubMed2004

Thrombospondin modules and angiogenesis.

Angiogenesis is a complex, multifactorial process that involves signals from endothelial cells and from the stoma. Extracellular matrix proteins participate in the modulation of growth factor response, contribute to the architecture of the vasculature and provide signals for the stabilization of mature capillary beds. The identification of the relevant extracellular matrix molecules and the characterization of their effects has been a central focus of research in vascular biology. Thrombospondin-1 is an extracellular glycoprotein first to be recognized as an inhibitor of angiogenesis more than a decade ago. Since then, much has been learned about its ability to regulate vascular growth in several angiogenesis models, functional domains have been identified, and mechanisms of action determined. This review summarizes current understanding on the effects of thrombospondin-1 and -2 during the process of angiogenesis. We will also extend our comments to ADAMTS1, a member of a relatively novel group of matrix metalloproteinases with thrombospondin repeats and shown to affect endothelial cell function and angiogenesis.

Animals↗
PubMed2005

Human peripheral blood eosinophils induce angiogenesis.

Eosinophils play a crucial role in allergic reactions and asthma. They are also involved in responses against parasites, in autoimmune and neoplastic diseases, and in fibroses. There is increasing evidence that angiogenesis plays an important role in these processes. Since eosinophils are known to produce angiogenic mediators, we have hypothesized a direct contribution of these cells to angiogenesis. The effect of human peripheral blood eosinophil sonicates on rat aortic endothelial cell proliferation (in vitro), rat aorta sprouting (ex vivo) and angiogenesis in the chick embryo chorioallantoic membrane (in vivo) have been investigated. To determine whether eosinophil-derived vascular endothelial growth factor influences the eosinophil pro-angiogenic activity, eosinophil sonicates were incubated with anti-vascular endothelial growth factor antibodies and then added to the chorioallantoic membrane. Vascular endothelial growth factor mRNA expression and vascular endothelial growth factor receptor density on the endothelial cells were also evaluated. Eosinophils were found to enhance endothelial cell proliferation and to induce a strong angiogenic response both in the aorta rings and in the chorioallantoic membrane assays. Pre-incubation of eosinophil sonicates with anti-vascular endothelial growth factor antibodies partially reduced the angiogenic response of these cells in the chorioallantoic membrane. Eosinophils also increased vascular endothelial growth factor mRNA production on endothelial cells. Eosinophils are able to induce angiogenesis and this effect is partially mediated by their pre-formed vascular endothelial growth factor. This strongly suggests an important role of eosinophils in angiogenesis-associated diseases such as asthma.

Animals↗
PubMed2005

A deterministic model of growth factor-induced angiogenesis.

Understanding the formation and structure of a capillary network is critical for any reparative strategy since the capillary network dictates tissue survival, hemodynamics, and mass transport. Vascular assembly and patterning has largely been studied using a reductionist approach where a particular endothelial cell molecular pathway or cellular mechanism is investigated as a relatively closed system. This trend of research has yielded a staggering wealth of genes, proteins, and cells that play critical roles in angiogenesis and some have resulted in successful targeted angiogenic therapies. However, these genes, proteins, and cells do not exist in discrete closed systems, rather they are intimately coupled across spatial and temporal dimensions. Designing experiments to study a single or group of perturbations is fraught with confounding complications. An integrative tool is required that incorporates gene, protein, and cell information and appropriately describes the complex systems behavior of vascular assembly and patterning. In this paper, we propose a new deterministic mathematical formulation to model growth factor-induced angiogenesis. Conductivity of the extracellular matrix for the movement/extension of capillary sprouts is a new concept introduced to account for the heterogeneity and anisotropy of the extracellular matrix. The replacement of traditional endothelial cell density by the capillary indicator function enhances the capabilities of capturing the capillary network sharply in a fine scale (i.e., tracking the dynamics of the tip in uni-cellular scale). Major mechanisms including cell proliferation, sprout branching, and anastomosis are incorporated directly into this continuous mathematical model and model parameters are perturbed to determine the strength of their effect on angiogenesis. The model is fully deterministic and generates the overall dendritic structure of the capillary network morphologically similar to those observed in vivo. The simulations "capture" significant vascular patterning, such as vascular loops and backward growth. Moreover, the simulations provide a deeper understanding of the influence of extracellular matrix on angiogenesis and vascular patterning. An advantage of this model is that the complex physical, chemical and biological processes in angiogenesis can be described and consequently analyzed by a mathematical system with self-contained information.

Animals↗
PubMed2004

p16 gene methylation lacks correlation with angiogenesis and prognosis in multiple myeloma.

Methylation of p16 gene is a relatively frequent molecular finding in multiple myeloma (MM), but its clinical implication is disputable. Cell cycle regulators are now recognized as active in the control of angiogenesis, which is an integral component of pathogenesis and a target for new treatment modalities of this disease. On such background, we focused on determining whether loss of p16 function by methylation could be associated with increased angiogenesis and VEGF expression, and the prognostic relevance of p16 methylation in 50 untreated, newly diagnosed MM patients. Thirty-one percent (13/42) of 42 patients assessable for p16 gene methylation showed to be methylation-positive. High-angiogenesis was present in 73% of cases, but methylation of the p16 gene did not associate with angiogenesis or with VEGF expression. Also, p16 methylation did not show prognostic relevance or correlation with the clinical and laboratory parameters of prognostic significance in univariate analysis. P16 immunoexpression presented only a faint agreement with the molecular study. Therefore, p16 methylation seems to have no correlation with angiogenesis and VEGF expression, neither with overall and event-free survival in MM patients. Besides, P16 immunohistochemistry seems inadequate to substitute the molecular study of methylation in this type of tumor cells. Additional studies are needed to clarify the correspondence between the epigenetic alteration of the p16 gene and its protein immunexpression, and the clinical relevance of p16 methylation in MM patients.

Adult↗
PubMed2005

Platelet-derived microparticles induce angiogenesis and stimulate post-ischemic revascularization.

OBJECTIVE: Platelet activation is accompanied by the release of microparticles. However, little is known about the role of platelet-derived microparticles (PMP) in the regulation of angiogenesis and related clinical situations. The aim of our study was to evaluate the effect of PMP on angiogenesis and to analyze its mechanisms. METHODS: Both in vitro (rat aortic ring model, cell invasion test) and in vivo (agarose bead transplantation, artificial cardiac ischemia in Sabra rats) approaches were used in the study. RESULTS: A dose-dependent pro-angiogenic effect of PMP was observed in the rat aortic ring model. This effect could be eliminated by inhibition of VEGF, bFGF, and PDGF, but not heparanase. PMP exerted their effect via PI 3-kinase, Src kinase, and ERK, whereas protein kinase C and p38 were not involved. Moreover, PMP induced invasion of endothelial cells through a layer of matrigel. This effect was mediated by VEGF, heparanase, and PDGF, but not bFGF. Furthermore, PMP induced angiogenesis in an in vivo model in which agarose beads containing PMP were transplanted subcutaneously into mice. In addition, the effect of PMP on angiogenesis was evaluated in the model of in vivo chronic myocardial ischemia in rats. Ischemia induced a decrease in the number of functioning capillaries (34+/-21.5 vs. 157+/-42.0 per view field), but their amount increased after injection of PMP into the myocarium (97+/-27.3; p<0.001 vs. ischemia without PMP). CONCLUSIONS: PMP induce angiogenesis both in vitro and in vivo. Injection of PMP into the ischemic myocardium might improve the process of revascularization after chronic ischemia.

Animals↗
PubMed2006

A plasmid DNA vaccine encoding the extracellular domain of porcine endoglin induces anti-tumour immune response against self-endoglin-related angiogenesis in two liver cancer models.

BACKGROUND: Anti-angiogenesis therapy has showed a promising future in tumour treatment. More and more evidence suggest that endoglin is a powerful marker of angiogenesis in solid malignancies, including liver cancer. AIM: To explore whether a plasmid DNA encoding the porcine endoglin has the ability of breaking immune tolerance against endoglin-related tumour angiogenesis in mice. METHODS: A eukaryotic plasmid encoding the extracellular domain of porcine endoglin was constructed, and then used it as a xenogeneic DNA vaccine. Hepa1-6 and H22 hepatoma models were established to observe the anti-tumour activities. Western blot, enzyme-linked immunoadsorbent assay and enzyme-linked immunospot assay were used to determine the antibody characters. Immunohistochemistry and alginate-encapsulated tumour cell assay were used to observe the anti-angiogenesis effects. RESULTS: Immunotherapy with recombinant plasmid encoding extracellular domain of porcine endoglin was effective at both protective and therapeutic anti-tumour immunity in two hepatoma models. Autoantibodies against murine endoglin were identified. IgG1 and IgG2b were the major subclasses in response to recombinant plasmid encoding extracellular domain of porcine endoglin vaccination. Anti-endoglin antibody-producing B cells were significantly increased in the spleens of mice immunised with recombinant plasmid encoding extracellular domain of porcine endoglin. In addition, mouse self-immunoglobulins were found deposited on the blood vessels of recombinant plasmid encoding extracellular domain of porcine endoglin-immunised tumour tissues. The similar anti-tumour activity was induced by the adoptive transfer of the purified immunoglobulins from the sera of mice immunised with recombinant plasmid encoding extracellular domain of porcine endoglin. Furthermore, angiogenesis was apparently inhibited within the tumour tissues from the recombinant plasmid encoding extracellular domain of porcine endoglin-immunised mice, and the vascularisation of alginate balls was also reduced in recombinant plasmid encoding extracellular domain of porcine endoglin-immunised mice. Most importantly, recombinant plasmid encoding extracellular domain of porcine endoglin could really induce cytotoxic T lymphocyte-mediated cytotoxicity and inhibit cell proliferation against endothelial cells. In addition, both CD4+ and CD8+ T lymphocytes took part in the function of inhibiting tumour growth and were synergistically responsible for induction of the anti-tumour activities. CONCLUSIONS: This approach may provide an alternative strategy for liver cancer immunotherapy.

Adoptive Transfer↗
PubMed2003

Angiogenesis in human cancer: implications in cancer therapy.

Angiogenesis represents an essential step in tumor proliferation, expansion, and metastasis. Tumor cells may express both proangiogenic and/or antiangiogenic factors. Under normal circumstances, angiogenesis is controlled through the equilibrium of these factors. This balance is disrupted in malignancy, resulting in promotion of angiogenesis. Among angiogenic molecules, VEGF appears to have a central role in the angiogenic process: it is the target of many proangiogenic factors, but it also regulates molecules that are implicated in endothelial proliferation. It has been suggested that VEGF may be a proximate angiogenic factor through which others act. The degree of angiogenesis and the expression of angiogenic factors have been associated with prognosis in several human neoplasms. In addition, angiogenesis offers a theoretically selective target for anticancer therapy, since it is only required for wound healing, endometrial proliferation, and pregnancy in healthy individuals. Antiangiogenic cancer treatment is still largely experimental and its clinical potential is currently being studied in clinical trials. Thalidomide, a drug with antiangiogenic properties, has shown significant efficacy in patients with relapsed or refractory multiple myeloma. In addition, an anti-VEGF monoclonal antibody prolonged survival in patients with advanced colorectal and renal cell carcinoma. Although these results are encouraging, selection of patients is essential in order to target populations most likely to benefit from antiangiogenic therapy.

Journal Article↗
PubMed2005

Inhibition of choroidal angiogenesis by calcium dobesilate in normal Wistar and diabetic GK rats.

Calcium dobesilate reduces vascular endothelial growth factor (VEGF) over-expression in diabetic rat retina, but its effect on intraocular angiogenesis is unknown. Therefore, we tested calcium dobesilate for its in vitro and ex vivo effects on choroidal explant angiogenesis in spontaneously diabetic Goto-Kakizaki (GK) rats. Choroidal explants were cultured in gels of collagen. Budded microvessels numbers and VEGF formation were taken as markers of angiogenesis. Ex vivo studies were performed in GK rats orally given 100 mg/kg/day calcium dobesilate for 10 days. In vitro, calcium dobesilate dose- and time-dependently inhibited both microvessel formation and VEGF production, at concentrations >or=25 mug/ml (i.e. >or=60 microM), with complete inhibition at 100 microg/ml. Oral treatment of diabetic GK rats with calcium dobesilate induced a significant reduction of choroidal angiogenesis ex vivo (38.8% after 3 days of culture). In conclusion, calcium dobesilate inhibited choroidal explant angiogenesis both in vitro and ex vivo. This effect may be due, at least in part, to inhibition of VEGF production. Antiangiogenesis by calcium dobesilate can be involved in its therapeutic benefit in diabetic retinopathy.

Animals↗