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PubMed2004

The functional role of blood platelet components in angiogenesis.

The process of neovascularization greatly depends on the induction of the angiogenic phenotype of endothelial cells that is strictly controlled by humoral factors as well as by cellular communications in the vascular system. Although blood platelets contain several secretable pro- and antiangiogenic components, their overall role in angiogenesis remains poorly understood. In a mouse model of hypoxia-induced retinal angiogenesis, the situation of thrombocytopenia as well as inhibition of platelet aggregation by a highly specific alphaIIbbeta3-integrin antagonist or acetyl salicylic acid (Aspirin) administration, respectively, resulted in about 35-50% reduction of retinal neovascularization, compatible with a significant contribution of blood platelets in angiogenesis. Platelet remnants and microvesicles were found at sites of angiogenic sprouts. In vitro isolated platelets incorporated in a fibrin gel induced capillary sprouting of microvascular endothelial cells. Similarly, platelet releasate elevated the permeability of confluent endothelial cell monolayers to the same extent as hypoxia did. Platelet-derived VEGF as well as butanol-extractable lipid mediators were identified as predominant activators of angiogenesis, particularly of microvascular endothelial cell proliferation and migration. In addition, a synergistic effect between platelet-derived VEGF and bFGF in capillary sprouting and endothelial cell proliferation was found. Based on this proangiogenic role of platelets in neovascularization, anti-platelet substances can be considered as potent inhibitors of angiogenesis.

Animals↗
PubMed2003

Molecular imaging of angiogenesis in nascent Vx-2 rabbit tumors using a novel alpha(nu)beta3-targeted nanoparticle and 1.5 tesla magnetic resonance imaging.

Early noninvasive detection and characterization of solid tumors and their supporting neovasculature is a fundamental prerequisite for effective therapeutic intervention, particularly antiangiogenic treatment regimens. Emerging molecular imaging techniques now allow recognition of early biochemical, physiological, and anatomical changes before manifestation of gross pathological changes. Although new tumor, vascular, extracellular matrix, and lymphatic biomarkers continue to be discovered, the alpha(nu)beta(3)-integrin remains an attractive biochemical epitope that is highly expressed on activated neovascular endothelial cells and essentially absent on mature quiescent cells. In this study, we report the first in vivo use of a magnetic resonance (MR) molecular imaging nanoparticle to sensitively detect and spatially characterize neovascularity induced by implantation of the rabbit Vx-2 tumor using a common clinical field strength (1.5T). New Zealand White rabbits (2 kg) 12 days after implantation of fresh Vx-2 tumors (2 x 2 x 2 mm(3)) were randomized into one of three treatment groups: (a) alpha(nu)beta(3)-targeted, paramagnetic formulation; (b) nontargeted, paramagnetic formulation; and (c) alpha(nu)beta(3)-targeted nonparamagnetic nanoparticles followed by (2 h) the alpha(nu)beta(3)-targeted, paramagnetic formulation to competitively block magnetic resonance imaging (MRI) signal enhancement. After i.v. systemic injection (0.5 ml of nanoparticles/kg), dynamic T(1)-weighted MRI was used to spatially and temporally determine nanoparticle deposition in the tumor and adjacent tissues, including skeletal muscle. At 2-h postinjection, alpha(nu)beta(3)-targeted paramagnetic nanoparticles increased MRI signal by 126% in asymmetrically distributed regions primarily in the periphery of the tumor. Similar increases in MR contrast were also observed within the walls of some vessels proximate to the tumor. Despite their relatively large size, nanoparticles penetrated into the leaky tumor neovasculature but did not appreciably migrate into the interstitium, leading to a 56% increase in MR signal at 2 h. Pretargeting of the alpha(nu)beta(3)-integrin with nonparamagnetic nanoparticles competitively blocked the specific binding of alpha(nu)beta(3)-targeted paramagnetic nanoparticles, decreasing the MR signal enhancement (50%) to a level attributable to local extravasation. The MR signal of adjacent hindlimb muscle or contralateral control tissues was unchanged by either the alpha(nu)beta(3)-targeted or control paramagnetic agents. Immunohistochemistry of alpha(nu)beta(3)-integrin corroborated the extent and asymmetric distribution of neovascularity observed by MRI. These studies demonstrate the potential of this targeted molecular imaging agent to detect and characterize (both biochemically and morphologically) early angiogenesis induced by minute solid tumors with a clinical 1.5 Tesla MRI scanner, facilitating the localization of nascent cancers or metastases, as well as providing tools to phenotypically categorize and segment patient populations for therapy and to longitudinally follow the effectiveness of antitumor treatment regimens.

Animals↗
PubMed1988

Evaluation of angiogenesis in chronic inflammation by laser-Doppler flowmetry.

1. A non-invasive method is described for the assessment of angiogenesis in chronic inflammation using laser-Doppler flowmetry. 2. Significant increases in capillary blood flow were seen on days 5 and 7 after induction of subcutaneous granulomatous lesions, as compared with control skin. 3. Changes in blood flow were accompanied by changes in pulsatile flow pattern and by an intense angiogenic response observed by light microscopy. 4. The potential application of laser-Doppler flowmetry to quantitative and qualitative studies of evolving angiogenesis in pathological responses is discussed.

Animals↗
PubMedDate not supplied

The HMG-CoA reductase pathway, statins and angioprevention.

Angiogenesis is one of the earliest and essential phenotypes acquired by tumors during carcinogenesis and thus might be a potential target for chemoprevention. Key to developing antiangiogenic chemoprevention is to identify new molecular targets and effective angiogenesis inhibitors. HMG-CoA reductase inhibitors, or statins, were originally designed to reduce cholesterol biosynthesis and have been extensively used as prevention drugs against hyperlipidemia and cardiovascular conditions. Recent research has found that statins promote endothelial death and inhibit experimental angiogenesis induced by growth factors or tumor, laying a foundation for developing statin-based angiopreventive strategies. This article reviews the biological effects of statins on endothelial cells and angiogenesis, possible underlying mechanisms and perspectives on future application of statins in preventing pathological angiogenesis.

Animals↗
PubMed1998

The significance of matrix metalloproteinases during early stages of tumor progression.

Matrix metalloproteinases (MMPs) orchestrate tissue remodeling and play diverse roles during organ development. They are produced excessively during the course of various pathological conditions, including solid tumors. An important function of MMPs during tumor progression is to provide the proteolytic activity that is necessary both for tumor cells to invade extracellular matrix (ECM) and for neovascularization of tumor tissue by endothelial cells. Recently, independent studies in transgenic animals suggest that MMPs may, in addition, promote very early stages of tumor progression. To investigate this possibility further, we have analyzed the consequences of MMP overexpression in functionally normal and nontumorigenic mouse mammary epithelial cells in culture. Our observations demonstrate that the MMP stromelysin-1 (SL-1) triggers an epigenetic molecular program in mammary epithelial cells that results in a number of phenotypic alterations that eventually culminate in the generation of a malignant tumor-cell phenotype.

Animals↗
PubMed2005

Preconditioning of arteriogenesis.

OBJECTIVE: Last decade, the shear stress caused by increased blood flow in collateral circulation after occlusion of main artery was recognized as a trigger of vascular remodeling and collateral growth. The goal of this study was to differentiate whether the on-going increased blood flow is necessary for the vascular remodeling or the remodeling, once in progress, develops independently of flow. METHODS: Femoral artery occlusion was performed in C57B1/6 mice. After 1-3 days, the ligature was removed and normal limb perfusion was re-established, monitored by laser Doppler Imaging (LDI). Two weeks after the first occlusion, both femoral arteries were re-occluded to compare collateral growth on the "naive" and "preconditioned" sides. After perfusion fixation, ultrastructural studies and morphometry of the collateral vessels were performed. RESULTS: Blood flow fell after occlusion to about 15% of control levels and recovered to about 40% by day 3. The reperfusion normalized sustainable blood flow. After the second occlusion, blood flow on both sides fell again to about 15% but recovered to 70% in the "preconditioned" compared to 40% in the "naive" side during the following 3 days. 5-Bromo-2'-desoxy-uridine (BrdU) administered during reperfusion was detected mainly in the neointima that, in many cases, had markedly narrowed the lumen. Two to three days after re-occlusion, a statistically significant lumen enlargement on the "preconditioned" side was observed, while neointima disappeared. CONCLUSION: Cellular proliferation and remodeling of collateral arteries were induced by short period of increased blood flow (occlusion of the femoral artery) but realized mostly during the low blood flow (reperfusion of the femoral artery). The neointima developing as a result of this remodeling can be recruited as a functional part of the arterial wall if the collateral perfusion increases as a result of repetitive occlusion of the femoral artery. The "medialization" of the neointima might cause the observed quicker gain of collateral lumen diameter and conductance, saving distal muscle tissue from the ischemia.

Animals↗
PubMed1997

Bullous lesions in Kaposi's sarcoma: case report.

Bullous lesions have been only rarely described in Kaposi's sarcoma (KS), and their histopathologic features have never been described in detail. We report a case of bullous lesions of KS in an 82-year-old Italian woman. The patient had typical smooth pale reddish-grey slightly-raised KS plaques on the legs, present for at least 10 years. Several dull grayish-pink blisters (0.5 to 2 cm in diameter) affected both dorsa of her feet and ankles symmetrically. Two punch biopsies were taken, one from an infiltrated KS plaque on the right buttock and the other from a bullous lesion on the right foot. Histopathologically, the late KS plaque on the buttock showed typical features of KS, with an increased number of spindle cells arranged in short bundles and extravasation of erythrocytes. The bullous lesion on the foot showed a full-thickness vascular neoplasm involving the upper and lower dermis and the subcutaneous fat. The upper portion of the lesion contained many newly formed, highly-dilated blood vessels, touching the overlying epidermis and separated from it by a narrow band of collagen and endothelial cells; wide, empty spaces characterized the superficial dermis, in which preexisting venules and bands of collagen associated with non-atypical endothelial cells floated. All these findings would suggest a lymphangiomatous lesion, if the presence of specific diagnostic criteria of KS were not recognizable at a deeper level of the lesion. Various criteria actually suggest that the bullous lesion may be regarded as an epiphenomenon of a KS plaque lesion: (a) full-thickness involvement of the reticular dermis and, in this case, also of the subcutaneous fat; (b) dense and patchy lymphoplasmocytic infiltrate typical of plaque lesions and, much less frequently, of patch lesions; (c) presence of ectatic blood vessels, filled with plasma and erythrocytes (pseudoangiomatous findings), a nonpathognomonic but highly characteristic finding of the plaque lesion; and (d) as in the KS plaque lesions, in the bullous lesion as well the reticular dermis was characterized by an increased number of anastomosing bizarrely shaped vascular spaces lined by non-atypical endothelial cells. We hypothesize that the prevalence of lymphangiomatous differentiation in the upper dermis represents one of the many features of KS lesions. When present, it may correlate with the clinical feature of a blister.

Adipose Tissue↗
PubMed2003

Regulation of heparanase gene expression by estrogen in breast cancer.

Numerous epidemiological studies clearly suggest that estrogen is one of the main driving forces in breast tumorigenesis, but precise mechanisms of cancer promotion by estrogen remain poorly understood. Classically, tumorigenic effects of estrogen have been attributed to its ability to directly promote the proliferation of breast cancer cells. In addition to abnormal proliferation, interactions between tumor cells and surrounding stromal components (e.g., enzymatic remodeling and degradation of extracellular matrix) are critical for cancer progression, angiogenesis, and metastasis. We now report that in breast carcinomas, estrogen may promote these pathological tumor-stromal interactions through up-regulation of heparanase gene expression. Heparanase is an endoglycosidase degrading heparan sulfate, of the basement membrane and extracellular matrix. This cleavage affects tumor-stromal interaction, neovascularization, local invasion, and metastatic spread. However, little is known about transcriptional regulation of the heparanase gene. We identified four putative estrogen response elements in the heparanase promoter region and found that transcription of a luciferase reporter gene driven by the heparanase promoter was significantly increased in estrogen-receptor positive MCF-7 human breast carcinoma cells after estrogen treatment. Estrogen-induced heparanase mRNA transcription in estrogen receptor-positive, but not in estrogen receptor-negative, breast cancer cells, confirmed the promoter study data. The estrogen effects on heparanase mRNA expression levels were abolished in the presence of the pure antiestrogen ICI 182,780, indicating that the classic estrogen receptor pathway is involved in transcriptional activation of heparanase. In vivo, exposure to estrogen augmented levels of heparanase protein in MCF-7 cells embedded in Matrigel plugs and correlated with increased plug vascularization. Collectively, our data suggest a new molecular pathway through which estrogen, independent of its proliferative effect, may induce heparanase overexpression and, thus, promote tumor-stromal interactions, critical for breast carcinoma development and progression.

Breast Neoplasms↗
PubMedDate not supplied

[Experimental models of angiogenesis for the study of the Ets1 transcription factor].

The Ets1 transcription factor gene is expressed in endothelial cells during blood vessel formation under normal or pathological conditions. The proposed hypothesis aims to involve Ets1 in the regulation of angiogenesis processes by activating the transcription of genes encoding matrix-degrading proteases. In vivo experiments allowing specific manipulation of ets1 gene expression or activity within endothelial cells are necessary to investigate the functional role of Ets1. Two experimental models using retroviruses expressing ets1 mutants have been chosen: Chicken embryo development and tumour-induced angiogenesis in mice. Another approach targeted on the vascular endothelium has been developed in order to obtain transgenic mice expressing specifically in endothelial cells an ets1 transdominant negative mutant under the control of the tek and tie promoters. These tools should allow interference with Ets1 activity at defined stages during normal or pathological development.

Animals↗
PubMed1996

Interstitial stroma and carcinogenesis: ultrastructural observations in the rat bladder treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

This study describes ultrastructural alterations of the interstitial stroma in the rat bladder epithelium during N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced bladder carcinogenesis using scanning (SEM) and transmission (TEM) electron microscopy with NaOH treatment. The results obtained with SEM demonstrated the occurrence and development of stroma protrusions which exhibited pipe-like structures in the rat bladder epithelium following administration of BBN. Number and size of blood vessel sections also gradually increased both in the stroma and within the layer of the proliferated epithelial cells as examined by light microscopy (LM) and TEM. In this study stroma alterations were not only observed in malignant lesions of rat bladder, but hyperplastic lesions were also accompanied by stroma alterations. It is suggested that: (1) the interstitial stroma of the rat bladder epithelium may exhibit pathological changes in structure and these changes may correlate with the progression of epithelial cell proliferation following administration of BBN and (2) one of the most important alterations in the stroma is the occurrence of neovascularization, which may induce structural modification of the stroma in the processes of bladder tumor growth and development.

Animals↗
PubMed1998

An unusual localization of massive portasystemic collaterals: CT angiographic demonstration.

This article presents a patient with portal hypertension in whom an unusual localization for portosystemic collaterals have incidentally been found. Upper abdominal sonography revealed tubular structures filling the whole perirenal and partially the perihepatic area, and their venous nature was demonstrated with duplex Doppler sonography. Spiral CT angiography identified the right-sided retroperitoneal location and mesenteric-lumbar route of the collaterals. Upper gastrointestinal endoscopy with antral biopsy and percutaneous liver biopsy were performed. Laboratory results and specimen evaluation revealed chronic active hepatitis due to hepatitis-B infection. Attention is drawn to the abnormal location of these vessels, together with the noninvasive nature and competence of CT angiography in demonstrating vascular pathologies.

Adult↗
PubMed1990

Inhibition of angiogenesis by vitamin D3 analogues.

The effects of vitamin D3 and two analogues on embryonic angiogenesis were studied in 4.5-day-old chick embryo chorioallantoic membranes. The active metabolite of vitamin D3, 1 alpha,25-dihydroxyvitamin D3, and a synthetic vitamin D3 analogue, 22-oxa-1 alpha,25-dihydroxyvitamin D3, inhibited angiogenesis in a dose-dependent manner, the inhibition occurring in the picomolar range. In contrast, vitamin D3 was not effective. The results suggest that these two vitamin D3 analogues might be promising anti-angiogenic agents for controlling the angiogenesis which occurs in several pathological conditions, including tumor development.

Animals↗
PubMed2003

Pigment epithelium-derived factor inhibits leptin-induced angiogenesis by suppressing vascular endothelial growth factor gene expression through anti-oxidative properties.

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. Recently, leptin was found to be an angiogenic factor, and its vitreous levels are associated with angiogenic eye diseases such as proliferative diabetic retinopathy. However, the molecular mechanism for leptin-elicited angiogenesis remains to be elucidated. Pigment epithelium-derived factor (PEDF) has been shown to be the most potent natural inhibitor of angiogenesis in the mammalian eye, and its levels in the vitreous were decreased in angiogenic eye diseases. In this study, we investigated whether and how PEDF could inhibit the leptin-induced DNA synthesis in microvascular endothelial cells (EC), a key step of angiogenesis. Leptin significantly increased intracellular reactive oxygen species (ROS) generation in microvascular EC. PEDF was found to inhibit the leptin-induced ROS generation in EC. An anti-oxidant, N-acetylcysteine, or PEDF completely prevented the leptin-induced upregulation of vascular endothelial growth factor (VEGF) mRNA levels as well as any increase in DNA synthesis in microvascular EC. Polyclonal antibodies against human VEGF were also found to completely inhibit DNA synthesis in leptin-exposed EC. The present study suggests that leptin could elicit angiogenesis through autocrine VEGF production via intracellular ROS generation. PEDF may block the angiogenic effects of leptin through its anti-oxidative properties.

Acetylcysteine↗
PubMed2003

Effect of allogeneic stem cell transplantation on bone marrow angiogenesis in chronic myelogenous leukemia.

Increased bone marrow angiogenesis is a poor prognostic marker in patients with chronic myelogenous leukemia (CML). Allogeneic stem cell transplantation (ASCT) can be curative for patients with CML. Studies in myeloma have shown persistent increased bone marrow microvessel density (MVD) after autologous transplantation. It is not clear if abnormal bone marrow angiogenesis persists following a curative intervention like allogeneic transplantation. We evaluated MVD from bone marrow samples obtained just prior to and at 3-5 months after ASCT in 24 patients with CML. The median MVD pre-transplant was 14 (4-37), with 11 patients having high-grade angiogenesis and 13 having low grade. The median post transplant MVD was 20 (range 5-36), with 12 patients having high-grade angiogenesis and 12 low grade. The median time between biopsies was 4 months (range 1-6 months). The microvessels in the post transplant bone marrow appeared morphologically different with striking dilatation and sinusoidal appearance compared to the pre-transplant marrow. However, there was no significant change in MVD following transplant (P=0.8, paired t-test). Abnormal bone marrow angiogenesis appears to persist in the bone marrow following ASCT for CML, at least in the short term.

Adult↗
PubMed2004

Endothelial cell integrins and COX-2: mediators and therapeutic targets of tumor angiogenesis.

Vascular integrins are essential regulators and mediators of physiological and pathological angiogenesis, including tumor angiogenesis. Integrins provide the physical interaction with the extracellular matrix (ECM) necessary for cell adhesion, migration and positioning, and induce signaling events essential for cell survival, proliferation and differentiation. Integrins preferentially expressed on neovascular endothelial cells, such as alphaVbeta3 and alpha5beta1, are considered as relevant targets for anti-angiogenic therapies. Anti-integrin antibodies and small molecular integrin inhibitors suppress angiogenesis and tumor progression in many animal models, and are currently tested in clinical trials as anti-angiogenic agents. Cyclooxygense-2 (COX-2), a key enzyme in the synthesis of prostaglandins and thromboxans, is highly up-regulated in tumor cells, stromal cells and angiogenic endothelial cells during tumor progression. Recent experiments have demonstrated that COX-2 promotes tumor angiogenesis. Chronic intake of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors significantly reduces the risk of cancer development, and this effect may be due, at least in part, to the inhibition of tumor angiogenesis. Endothelial cell COX-2 promotes integrin alphaVbeta3-mediated endothelial cell adhesion, spreading, migration and angiogenesis through the prostaglandin-cAMP-PKA-dependent activation of the small GTPase Rac. In this article, we review the role of integrins and COX-2 in angiogenesis, their cross talk, and discuss implications relevant to their targeting to suppress tumor angiogenesis.

Angiogenesis Inhibitors↗