PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Neovascularization, Pathologic”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 253 records · Page 14Linked to original sources
PubMed1999

Gene regulation and arteriosclerosis: are developmental programs reactivated in vascular disease?

The molecular mechanisms regulating the development of vascular diseases such as atherosclerosis remain poorly understood at present. Similarities between genetic programs observed during the course of vascular disease with those observed during vascular development suggest that developmental processes are recapitulated in vascular disease. The earliest event in vascular development is the differentiation of endothelial cells from their mesodermally-derived hemangioblastic precursors. The receptor for vascular endothelial growth factor, KDR/flk-1, plays a critical role in these earliest stages of vascular development. During development and in the adult, expression of this receptor is restricted to vascular endothelial cells and their immediate precursors. We have therefore endeavored to determine the transcriptional events regulating KDR/flk-1 expression, with the hope of gaining insight into processes of vascular development that might also be important in vascular diseases of the adult.

Adult↗
PubMed2000

Determinants of endothelial cell phenotype in venules.

Inflammatory stimuli cause plasma leakage and leukocyte adhesion in venules but not in capillaries or arterioles. The specific response of venules is governed by phenotypic specialization of the venular endothelial cells. What regulates this specialized phenotype? Several recent developments have shed new light on this question and may challenge our thinking about regulation of the venular endothelial cell phenotype. In this review, we consider some of the molecular markers of venular endothelial cells, the hemodynamic and molecular factors that may regulate the phenotype of venular endothelial cells, and abnormalities in endothelial cell phenotype in disease-related angiogenesis and microvascular remodeling. The expanding list of molecular markers may help clarify the physiologic and molecular factors that regulate the phenotype of venular endothelial cells in normal development and disease.

Angiopoietin-1↗
PubMed2000

Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer.

To reveal the antiangiogenic capability of cancer chemotherapy, we developed an alternative antiangiogenic schedule for administration of cyclophosphamide. We show here that this antiangiogenic schedule avoided drug resistance and eradicated Lewis lung carcinoma and L1210 leukemia, an outcome not possible with the conventional schedule. When Lewis lung carcinoma and EMT-6 breast cancer were made drug resistant before therapy, the antiangiogenic schedule suppressed tumor growth 3-fold more effectively than the conventional schedule. When another angiogenesis inhibitor, TNP-470, was added to the antiangiogenic schedule of cyclophosphamide, drug-resistant Lewis lung carcinomas were eradicated. Each dose of the antiangiogenic schedule of cyclophosphamide induced the apoptosis of endothelial cells within tumors, and endothelial cell apoptosis preceded the apoptosis of drug-resistant tumor cells. This antiangiogenic effect was more pronounced in p53-null mice in which the apoptosis of p53-null endothelial cells induced by cyclophosphamide was so vigorous that drug-resistant tumors comprising 4.5% of body weight were eradicated. Thus, by using a dosing schedule of cyclophosphamide that provided more sustained apoptosis of endothelial cells within the vascular bed of a tumor, we show that a chemotherapeutic agent can more effectively control tumor growth in mice, regardless of whether the tumor cells are drug resistant.

Animals↗
PubMed2000

Gene targeting and gene transfer to unravel the molecular basis of the formation and disorders of blood vessels.

Novel gene technologies have allowed to manipulate the genetic balance of candidate molecules in mice in a controllable manner. Homologous or site-specific recombination in embryonic stem cells allows to study the consequences of deficiencies, mutations, conditional or tissue specific expression of gene products in transgenic mice. These technological breakthroughs have significantly advanced biomedical research and our understanding of the pathophysiological role of candidate disease genes. In addition, gene transfer allows to test the possible therapeutic use of gene products for gene therapy. With the advent of genome sequencing programs, these gene technologies provide means to study gene function in a conclusive manner. Furthermore, disease models can be generated which can be used as testmodels for (gene) therapy or for discovery of novel genes using differential gene profiling techniques. The present review will focus on the use of these technologies to study the molecular basis of how blood vessels form (angiogenesis) and how vessels can become affected by disorders. A selected number of molecules that have been studied in our laboratory will be reviewed in particular.

Adult↗
PubMed2000

Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression.

Although several CXC chemokines have been shown to induce angiogenesis and play roles in tumor growth, to date, no member of the CC chemokine family has been reported to play a direct role in angiogenesis. Here we report that the CC chemokine, monocyte chemotactic protein 1 (MCP-1), induced chemotaxis of human endothelial cells at nanomolar concentrations. This chemotactic response was inhibited by a monoclonal antibody to MCP-1. MCP-1 also induced the formation of blood vessels in vivo as assessed by the chick chorioallantoic membrane and the matrigel plug assays. As expected, the angiogenic response induced by MCP-1 was accompanied by an inflammatory response. With the use of a rat aortic sprouting assay in the absence of leukocytic infiltrates, we ruled out the possibility that the angiogenic effect of MCP-1 depended on leukocyte products. Moreover, the direct effect of MCP-1 on angiogenesis was consistent with the expression of CCR2, the receptor for MCP-1, on endothelial cells. Assessment of supernatant from a human breast carcinoma cell line demonstrated the production of MCP-1. Treatment of immunodeficient mice bearing human breast carcinoma cells with a neutralizing antibody to MCP-1 resulted in significant increases in survival and inhibition of the growth of lung micrometastases. Taken together, our data indicate that MCP-1 can act as a direct mediator of angiogenesis. As a chemokine that is abundantly produced by some tumors, it can also directly contribute to tumor progression. Therefore, therapy employing antagonists of MCP-1 in combination with other inhibitors of angiogenesis may achieve more comprehensive inhibition of tumor growth.

Allantois↗
PubMed2000

CXC chemokines in angiogenesis.

A variety of factors have been identified that regulate angiogenesis, including the CXC chemokine family. The CXC chemokines are a unique family of cytokines for their ability to behave in a disparate manner in the regulation of angiogenesis. CXC chemokines have four highly conserved cysteine amino acid residues, with the first two cysteine amino acid residues separated by one non-conserved amino acid residue (i.e., CXC). A second structural domain within this family determines their angiogenic potential. The NH2 terminus of the majority of the CXC chemokines contains three amino acid residues (Glu-Leu-Arg: the ELR motif), which precedes the first cysteine amino acid residue of the primary structure of these cytokines. Members that contain the ELR motif (ELR+) are potent promoters of angiogenesis. In contrast, members that are inducible by interferons and lack the ELR motif (ELR-) are potent inhibitors of angiogenesis. This difference in angiogenic activity may impact on the pathogenesis of a variety of disorders.

Amino Acid Motifs↗
PubMed2000

Expression of the hypoxically regulated angiogenic factor adrenomedullin correlates with uterine leiomyoma vascular density.

Uterine leiomyomas are the most prevalent benign tumor type in women of reproductive age and are one of the most common indications for hysterectomy. The expression of five angiogenic factors, adrenomedullin (ADM), vascular endothelial growth factor (VEGF), acidic fibroblast growth factor, basic fibroblast growth factor, and platelet-derived endothelial cell growth factor/thymidine phosphorylase, were examined in 91 uteri collected throughout the menstrual cycle; 52 of which contained leiomyomata, and the remainder were normal controls. The microvascular density and endothelial proliferative indices were then determined for each of the uterine sections. ADM and VEGF were the most widely expressed angiogenic factors in the leiomyomas. Furthermore, the expression of ADM and VEGF in the endometrium and myometrium was up-regulated in leiomyoma-bearing uteri compared with controls. Although acidic fibroblast growth factor and basic fibroblast growth factor were expressed in leiomyomas and endometrium in all of the uterine samples examined, they were only expressed in the myometrium of leiomyomata-bearing uteri. Endothelial proliferation in leiomyomas was statistically greater than that of the myometrium and endometrium, both within and between uteri (P < 0.05). The vascular density in the myometrium but not the endometrium was significantly increased in leiomyoma-containing uteri (P < 0.05). Expression of ADM alone correlated directly with vascular density and endothelial cell proliferation index in leiomyomas and myometrium and may account for the high vascularity found in leiomyomas and the myometrium of leiomyoma-bearing uteri. As such, ADM is identified as a novel target for antiangiogenic therapy of these benign, clinically problematic uterine tumors.

Adrenomedullin↗
PubMed2000

Inhibition of tumor angiogenesis by a single-chain antibody directed against vascular endothelial growth factor.

Monoclonal antibody (Ab) directed against the vascular endothelial growth factor, one of the major inducers of angiogenesis, can inhibit tumor growth in mice. Treatment of cancer patients with monoclonal Ab requires large-scale production of the clean Ab and frequent application of the Ab. This might be improved by using single-chain Ab fragments (scFvs), which can be produced in large quantities in bacteria and are attractive for gene therapeutic approaches. Here we describe anti-vascular endothelial growth factor scFvs derived from a human phage-display library able to block the vascularization of the chorioallantoic membrane of chick embryos and reduce the growth of s.c. tumors in nude mice. This work opens the way to develop gene therapy-based strategies using a scFv to treat angiogenesis-dependent diseases.

3T3 Cells↗
PubMed2000

Angiogenin expression in human colorectal cancer: the role of focal macrophage infiltration.

Tumor angiogenesis is essential for tumor growth and tumor metastasis, and it depends on angiogenic factors produced by tumor cells and/or infiltrating cells in tumor tissue. In this study, we evaluated the clinical significance of the expression of angiogenin, which is a potent angiogenic protein, and the relationship between its mRNA expression and focal macrophage infiltration in colorectal cancer. Furthermore, we investigated the induction of angiogenin mRNA expression by proinflammatory cytokines mainly produced by inflammatory cells in tumor tissues. When we examined the relationship between the mRNA expression of angiogenin, by semiquantitative reverse transcription-PCR, and clinicopathological features in 65 patients with colorectal cancer, there was a significant difference in the vascular involvement, lymph node metastasis, liver metastasis, and advanced stage in patients with high-expression of angiogenin compared with low expression (P < 0.05). With regard to prognosis, the survival time for subjects in the high angiogenin mRNA group (tumor:normal ratio >1.9) was significantly worse (P < 0.05). When we examined the localization of angiogenin in colorectal cancer, immunohistochemical analysis in 65 patients with colorectal cancer revealed that angiogenin was predominantly expressed in cancer cells compared with stromal cells or normal tissues. The intensity of staining of angiogenin was significantly correlated with microvessel counts and focal macrophage infiltration counts (P < 0.05). In an in vitro study, interleukin-1beta and tumor necrosis factor-alpha induced angiogenin mRNA expression in colon cancer cells in a dose- and time-dependent manner, and these cytokines significantly upregulated the expression of angiogenin mRNA, especially in colon cancer cells rather than in other cells in the stroma of tumor tissues (fibroblasts, tumor infiltrating lymphocytes, macrophages). These results suggest that tumor angiogenesis in colorectal cancer may be advanced, at least in part, by angiogenin induced by proinflammatory cytokines derived from infiltrating macrophages.

Colorectal Neoplasms↗
PubMed2000

Monoclonal antibody to vascular endothelial-cadherin is a potent inhibitor of angiogenesis, tumor growth, and metastasis.

Vascular endothelial-cadherin (VE-cad) is an endothelial cell-specific adhesion molecule that is crucial for proper assembly of vascular tubes. Here we show that a monoclonal antibody (BV13) directed to the extracellular region of VE-cad inhibits formation of adherens junctions and capillary-like structures by endothelial cells and blocks angiogenesis in the mouse cornea and in Matrigel plugs in vivo. Systemic administration of BV13 markedly decreases the growth of s.c. Lewis lung or human A431 epidermoid tumors and strongly suppresses the growth of Lewis lung metastases. These data demonstrate that VE-cad is essential for postnatal angiogenesis and thus validate VE-cad as a novel target for antiangiogenesis agents.

Animals↗
PubMedDate not supplied

Anti-invasive activity of torilin, a sesquiterpene compound isolated from Torilis japonica.

Torilin is a sesquiterpene compound purified from Torilis japonica (Umbelliferae). We have previously reported that torilin has a potent anti-angiogenic activity both in vivo and in vitro. In the present study, we investigated the anti-invasive activity of torilin, and interestingly found that torilin completely blocked intravasation of HT1080 human fibrosarcoma cells inoculated on the chorioallantoic membrane (CAM) of chick embryo. In addition, torilin decreased the attachment of HT1080 cells to confluent human umbilical vein endothelial cells (HUVECs) at non-toxic concentration. In in vitro transwell invasion model, 25 microM torilin also significantly inhibited HT1080 cell invasion in a time-dependent manner. Activity and expression of matrix metalloproteinase-9 (MMP-9) that is very important in tumor invasion and metastasis were also decreased by torilin treatment, indicating that the inhibitory effect of torilin on invasion of HT1080 cells may result from decreasing activity and expression of MMP-9. Therefore, it is possible that torilin may decrease metastatic potential of tumor cells through inhibiting their attachment to endothelial cells and intravasation to blood vessels. Taken together, torilin may have a strong activity to suppress tumorigenesis by inhibition of tumor invasion.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Vascular endothelial growth factor (VEGF) and its effect on angiogenesis.

The article discusses the role of vascular endothelial growth factor(VEGF) in angiogenesis in embryonic development, particularly the effect of VEGF on capillary formation in response to chronic tissue ischemia and hypoxia. The sources and action of numerous angiogenic and angiostatic factors responsible for morphologic development of endothelial cells and disturbances in VEGF and FGF secretion are also presented. Increased VEGF and VEGF receptor expression enhances vascular permeability and angiogenesis, and is the cause of tissue edema as well as tumor and metastasis formation. VEGF appears to have a beneficial effect only in ischemic diseases of the heart and peripheral vessels. The article highlights the therapeutic implication of VEGF suppression in other areas of ischemia.

Animals↗
PubMed2000

Adenosine and chronic ischemia of the lower limbs.

Adenosine is an endogenous nucleoside with multiple biological properties which plays a central role in the pathophysiology of tissue ischemia. Adenosine signals an imbalance between oxygen demand and supply, and it initiates responses to redress such a discrepancy. Besides its vasodilating properties, adenosine possesses anti-platelet and anti-neutrophil activities and provides cytoprotection. Adenosine is presumably the main mediator of the preconditioning phenomenon. During ischemia of the lower limbs, adenosine plays a physiological role by inducing vasodilatation and by preventing microcirculatory failure. Exercise training prolongs claudication distance possibly by inducing pulse increases of adenosine and consequently skeletal muscle preconditioning. Moreover, the adenosine increase which follows the administration of some drugs, such as buflomedil and propionylcarnitine, opens new perspectives in the management of leg ischemia. In fact, the concept arises of an ischemic (exercise-dependent) or pharmacologic preconditioning in the treatment of patients with claudication.

Adenosine↗
PubMed2001

Inhibition of angiogenesis and tumor growth by SCH221153, a dual alpha(v)beta3 and alpha(v)beta5 integrin receptor antagonist.

New blood vessel formation is essential for tumor growth and metastatic spread. Integrins alpha(v)beta3 and alpha(v)beta5 are arginine-glycine-aspartic acid-dependent adhesion receptors that play a critical role in angiogenesis. Hence, selective dual alpha(v)beta3 and alpha(v)beta5 antagonists may represent a novel class of angiogenesis and tumor-growth inhibitors. Here, an arginine-glycine-aspartic acid-based peptidomimetic library was screened to identify alpha(v)beta3 antagonists. Selected compounds were then modified to generate potent and selective dual inhibitors of alpha(v)beta3 and alpha(v)beta5 receptors. One of these compounds, SCH 221153, inhibited the binding of echistatin to alpha(v)beta3 (IC50 = 3.2 nM) and alpha(v)beta5 (IC50 = 1.7 nM) with similar potency. Its IC50 values for related alpha(IIb)beta3 and alpha5beta1 receptors were 1294 nM and 421 nM, respectively, indicating that SCH 221153 is highly selective for alpha(v)beta3 and alpha(v)beta5 receptors. In cell-based assays, SCH 221153 inhibited the binding of echistatin to alpha(v)beta3- and alpha(v)beta5-expressing 293 cells and blocked the adhesion of endothelial cells to immobilized vitronectin and fibroblast growth factor 2 (FGF2). SCH 221153, but not the inactive analogue SCH 216687, was effective in inhibiting FGF2 and vascular endothelial growth factor-induced endothelial cell proliferation in vitro with an IC50 equal to 3-10 microM. Angiogenesis induced by FGF2 in the chick chorioallantoic membrane assay was also inhibited by SCH 221153. Finally, SCH 221153 exerted a significant inhibition on tumor growth induced by intradermal or s.c. injection of human melanoma LOX cells in severe combined immunodeficient mice.

Allantois↗
PubMed2001

The angiogenesis inhibitor tnp-470 effectively inhibits human neuroblastoma xenograft growth, especially in the setting of subclinical disease.

Tumor vascularity is highly correlated with disease outcome in neuroblastoma. Thus, novel therapeutics that target the vascular endothelium are candidates for incorporation into clinical trials. We therefore examined the effect of TNP-470 on human neuroblastoma growth in mouse models reflecting both clinically evident and minimal disease. Mice were inoculated s.c. or by tail vein injection with 10(7) human neuroblastoma-derived CHP-134 cells and treated with TNP-470 (100 mg/kg/dose s.c. three times a week or by continuous infusion) or saline. Treatment was given as a single agent in established xenografts, 10 days after 450 mg/kg of cyclophosphamide, or 12 h after tumor inoculation. Tumor growth rate was markedly inhibited in mice receiving TNP-470 administered alone both s.c. and by continuous infusion with a treatment to control ratio (T:C) at day 16 of 0.3 (P < 0.001) and a T:C at day 30 of 0.4 (P = 0.029) for each dosing method, respectively. TNP-470 also significantly inhibited tumor growth when administered following cyclophosphamide (T:C at day 30 = 0.2, P < 0.001) and inhibited disease establishment when given shortly after xenograft inoculation (T:C at day 30 = 0.1, P < 0.001) or tail vein injection. TNP-470 was shown to directly inhibit angiogenesis by Matrigel assay (P =.010) and to increase the apoptotic index in treated tumors. These data show that TNP-470 is a potent inhibitor of human neuroblastoma growth rate and tumorigenicity. We speculate that TNP-470 may be a useful adjuvant therapy for high-risk neuroblastoma patients, particularly when used in settings of minimal disease status.

Angiogenesis Inhibitors↗