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Results for “Neovascularization, Pathologic”

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PubMed2006

Targeting the inflammatory response in healing myocardial infarcts.

Healing of myocardial infarcts depends on an inflammatory cascade that ultimately results in clearance of dead cells and matrix debris and formation of a scar. Myocardial necrosis activates complement, Nuclear Factor (NF)-kappaB and Toll-like Receptor (TLR)-dependent pathways, and generates free radicals, triggering an inflammatory response. Chemokines and cytokines are markedly induced in the infarct and mediate recruitment and activation of neutrophils and mononuclear cells. Extravasation of platelets and plasma proteins, such as fibrinogen and fibronectin, results in formation of a clot, consisting of platelets embedded in a mesh of crosslinked fibrin. This provisional matrix provides a scaffold for migration of cells into the infarct. Monocytes differentiate into macrophages and secrete fibrogenic and angiogenic growth factors inducing formation of granulation tissue, containing myofibroblasts and neovessels. Repression of proinflammatory cytokine and chemokine synthesis, mediated in part through Transforming Growth Factor (TGF)-beta and Interleukin (IL)-10, is critical for resolution of the inflammatory infiltrate and transition to fibrous tissue deposition. Infarct myofibroblasts deposit extracellular matrix proteins and a collagen-based scar is formed. As the wound matures, fibroblasts undergo apoptosis and neovessels regress, resulting in formation of a scar with a low cellular content containing dense, cross-linked collagen. The pathologic and structural changes associated with infarct healing directly influence ventricular remodeling and affect prognosis in patients with myocardial infarction. Understanding the mechanisms involved in the regulation of the post-infarction inflammatory response, and the spatial and temporal parameters of wound healing is necessary in order to identify specific molecular targets for therapeutic intervention.

Chemokines↗

PubMed2004

Serum levels of IGF-I, HGF, TGFbeta1, bFGF and VEGF in thyroid gland tumors.

IGF-I, HGF, TGFbeta1, bFGF and VEGF are involved in the pathogenesis of thyroid gland tumors and their growth. We decided to find whether changes in the production of these cytokines by thyroid tumor cells are reflected by changes of their peripheral blood. Using ELISA kits, we measured the concentrations of growth factors in the peripheral blood serum in 28 patients with thyroid gland tumors (14 adenomas, 14 papillary carcinomas) and compared these concentrations with those in healthy people. We found significantly lower serum levels of IGF-I in patients with thyroid adenoma compared to the healthy population. Serum levels of HGF and bFGF were significantly higher in patients with thyroid adenoma and papillary carcinoma compared with those in healthy subjects. Serum concentrations of TGFbeta1 and VEGF were not significantly different in any groups of investigated subjects. Changes in the production of these cytokines by thyroid gland tumor cells are reflected in their peripheral blood levels, but these levels also depend on a number of other physiological and pathological processes in the organism. However, significant differences of HGF and bFGF serum levels can be explained by their very high production by thyroid tumor cells and by their strong effect on the follicular and endothelial cell proliferation.

Adenoma↗

PubMed2001

The angiogenic pathway "vascular endothelial growth factor/flk-1(KDR)-receptor" in rheumatoid arthritis and osteoarthritis.

Active angiogenesis, together with an up-regulation of angiogenic factors, is evident in the synovium of both rheumatoid arthritis (RA) and osteoarthritis (OA). The present study assessed, by immunohistochemistry, the microvessel density in the synovium of these arthritides and in normal controls, in relation to the expression of the angiogenic factors vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) and the apoptosis-related proteins bcl-2 and p53. More importantly, using the novel 11B5 MAb, the activated "VEGF/flk-1(KDR)-receptor" microvessel density was assessed. VEGF expression in fibroblasts was diffuse in both RA and OA. Diffuse PD-ECGF expression of fibroblasts was noted in all cases of RA, while fibroblast reactivity was focal in the OA material. The standard microvessel density (sMVD), as assessed with the anti-CD31 monoclonal antibody (MAb), was higher in RA (64+/-12) and in OA (65+/-16) than in normal tissues (52+/-8; p=0.008 and 0.0004, respectively). The activated microvessel density (aMVD), assessed with the 11B5 MAb, was significantly higher in RA (29+/-10) than in OA (17+/-4; p<0.0001) and than in normal tissues (14+/-2; p<0.0001). The "activation ratio" (aMVD/sMVD) was statistically higher in RA (0.46+/-0.17) than in OA and normal synovial tissues, the latter two having a similar ratio (0.28+/-0.08 and 0.26+/-0.03, respectively). Cytoplasmic bcl-2 expression was frequent in the synovial cells of OA, but rare in RA. Nuclear p53 protein accumulation was never observed. It is suggested that the angiogenic pathway VEGF/flk-1(KDR) may play an important role in the pathogenesis of RA and OA. Thus, failure of VEGF/flk-1(KDR) activation, in the presence of increased VEGF expression, may indicate a synovium with an impaired capacity to establish a viable vasculature, consistent with the degenerative nature of OA. On the other hand, the activated angiogenesis in RA shows a functional, still pathologically up-regulated VEGF/flk-1(KDR) pathway. Whether restoration of an impaired VEGF/flk-1(KDR) pathway in OA, or inhibition of this in RA, would prove of therapeutic importance requires further investigation.

Adult↗

PubMed2004

The natural progression of microvasculature in primary tumor and lymph node metastases in a breast carcinoma model: relationship between microvessel density, vascular endothelial growth factor expression, and metastatic invasion.

The natural course of tumor microvascularity in rat MTLn3 mammary adenocarcinomas was studied. The relationship between microvessel density (MVD), vascular endothelial growth factor (VEGF) expression, and histopathology was compared in primary and metastatic axillary (ALN) and inguinal lymph node (ILN) tumors over 5-6 tumor doublings. Excised tumors were examined for (i) MVD assessed by immunostaining with anti-CD31 antibody, (ii) VEGF expression assessed by immunostaining with anti-VEGF antibody, and (iii) histopathologic extent of metastatic lymph node invasion. MVD and VEGF scores rose asymptotically with increasing tumor weight in both primary and metastatic tumors. The MVD saturation level was significantly greater for primary tumors (MVD = 22) than for ALNs or ILNs (MVD = 14). Maximal VEGF score was not statistically different between the three kinds of tumors, however the rate of rise in VEGF expression was different. Near-maximal VEGF expression occurred early in tumor growth, preceding microvessel development. Both MVD and VEGF expression in lymph nodes were proportional to the pathology score characterizing increasing metastatic invasion. LNMs limited to the subcapsular sinus had the lowest MVD, indicating an ability to survive without significant vasculature. These findings underscore the differences in angiogenesis between primary tumors and LNMs and have implications for therapy of metastatic cancer.

Animals↗

PubMed1996

Pathology, genetics and cell biology of hemangioblastomas.

Hemangioblastomas are highly vascularized tumors of not well-defined histological origin which are frequently associated with cysts. They arise preferentially in cerebellum, medulla and spinal cord and are histologically indistinguishable from vascular lesions in the retina (so-called angiomatosis retinae). Hemangioblastomas are the most frequent manifestations of the von Hippel-Lindau (VHL) disease, an autosomal-dominant inherited cancer syndrome but also occur as sporadic non-hereditary tumors. The VHL tumor suppressor gene has recently been cloned and enormous progress has been made towards the understanding of molecular biology and biological function of the VHL gene. Germline mutations in VHL patients, as well as somatic mutations in different tumors, including hemangioblastomas, have been identified, its ability to act as a tumor suppressor in vivo has been confirmed, and interaction with transcription factors Elongin B and C leading to inhibition of transcriptional elongation has been demonstrated. The mechanism underlying neovascularization and cyst formation in hemangioblastomas and how this is linked to inactivation of the VHL tumor suppressor gene is not known. However, the finding of dramatic up-regulation of vascular endothelial growth factor (VEGF), a potent endothelial cell growth factor with vascular permeability-inducing activity, in stromal cells and the corresponding receptors, VEGFR-1 and VEGFR-2, in tumor endothelial cells suggests that angiogenesis and cyst formation in hemangioblastomas may be regulated by this signaling pathway via a paracrine mechanism.

Brain Neoplasms↗

PubMed1990

Outcome of iatrogenic choroidal neovascularisation in sickle cell disease.

Choroidal neovascularisation developed in 62/66 (94%) eyes followed up for a mean period of 11.2 years after treatment with xenon arc feeder vessel coagulation for proliferative sickle retinopathy (PSR). In 27 eyes the neovascularisation was chorioretinal alone and in 35 eyes choriovitreal. Chorioretinal neovascularisation (CRN) was a benign complication but may convert to choriovitreal neovascularisation (CVN). Late sequelae of CVN included vitreous haemorrhage, posterior vitreous face fibrosis, and tractional retinal detachment. Visual loss (of greater than or equal to 3 Snellen lines for greater than or equal to 3 months) occurred in nine eyes affected by choroidal neovascularisation, though because of other pathology this could not always be attributed to the choroidal neovascularisation. The incidence of visual loss in CVN affected eyes was significantly greater, by survival curve analysis, than in eyes affected by CRN alone. Permanent visual loss from tractional retinal detachment definitely attributable to CVN occurred in 2/35 (6%) eyes.

Adolescent↗

PubMed2005

Epidural angiolipoma is histologically distinct from its cutaneous counterpart in the calibre and density of its vascular component; a case report with review of the literature.

Angiolipoma of the spine is a rare tumour and no studies have investigated a sufficient number of cases to reach general conclusions. Therefore, as yet, the pathological definition of this entity is not well established. The case of epidural angiolipoma reported here and a review of the literature revealed that this entity is distinct from cutaneous angiolipoma in that the calibre of its predominant vascular component is far greater than that of the fat cells. Therefore, epidural angiolipoma can be regarded as not only topographically, but also histologically, distinct from its subcutaneous counterpart.

Aged↗

PubMed1999

Neutrophil activation and mediators of inflammation in chronic venous insufficiency.

The effect of venous hypertension on the state of activation of leucocytes has been investigated in patients with venous disease and control subjects. Leucocytes become 'trapped' in the circulation of the leg during periods of venous hypertension produced by sitting or standing. This is greater in the limbs of patients with chronic venous disease than controls. Studies of the plasma levels of neutrophil granule enzymes show that these are increased during periods of venous hypertension, suggesting that this causes activation of the neutrophils. Investigation of the leucocyte surface ligand CD11b shows that the more activated neutrophils and monocytes are sequestered during venous hypertension. Measurement of plasma levels of the soluble parts of the vascular (VCAM), intercellular (ICAM) and endothelial leucocyte (ELAM) adhesion molecules show that these are all elevated in patients with chronic venous disease compared to controls. Following 30 min of venous hypertension produced by standing, these levels are further increased. These data suggest that venous hypertension causes neutrophil and monocyte activation, which in turn causes injury to the endothelium. I believe that this may be the mechanism that initiates the pathological processes which lead to venous ulceration. It has recently been shown that the venotonic drug Daflon 500 mg (450 mg diosmin, 50 mg hesperidin, Servier, France) influences these processes. Surface expression of CD62L is reduced in neutrophils and monocytes, and plasma levels of soluble endothelial adhesion molecules are reduced. These observations may explain the anti-inflammatory effects of Daflon 500 mg.

Animals↗

PubMed1995

The role of vascular endothelial growth factor in pathological angiogenesis.

Vascular endothelial growth factor (VEGF) is a diffusible endothelial cell-specific mitogen and angiogenic factor that can also increase vascular permeability. By alternative splicing of mRNA, VEGF may exist as one of four different isoforms that have similar biological activities but differ markedly in targeting and bioavailability. The VEGF receptors are specifically expressed in the cell surface of vascular endothelial cells. Recent studies point to VEGF as a major regulator of physiological angiogenesis, such as developmental and reproductive angiogenesis. Furthermore, VEGF appears to be a crucial mediator of blood vessel growth associated with tumors and proliferative retinopathies. The VEGF mRNA is up-regulated in the majority of human tumors and the VEGF protein is increased in the aqueous and vitreous humors of patients with proliferative retinopathies. Anti-VEGF antibodies have the ability to suppress the growth of a variety of tumor cell lines in nude mice and also can inhibit angiogenesis in animal models of intraocular neovascularization. Therefore, strategies aimed at antagonizing VEGF may form the basis for an effective treatment of tumors and retinopathies. Furthermore, VEGF-induced angiogenesis is sufficient to achieve a therapeutic endpoint in models of coronary or limb ischemia.

Animals↗

PubMed1998

Growth factor-mediated angiogenesis in the malignant progression of glial tumors: a review.

BACKGROUND: We review the role of peptide growth factors in angiogenesis and progression of low grade glial tumors to higher grade glioblastoma multiforme (GBM). METHODS: Vascular pathology is a key feature of glioblastoma multiforme characterized by hypervascularity, vascular permeability, and hypercoagulability. RESULTS: Vascular endothelial growth factor (VEGF) can mediate all of these effects, but by itself does not promote malignant growth. Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and transforming growth factor beta (TGF-beta) are implicated in the angiogenesis of a number of tumors including those of glial origin. CONCLUSIONS: These growth factors are suggested to play a role in autocrine and/or paracrine mediated tumorogenesis of astrocytic tumors. VEGF secretion might be the product of induction by physiologic concentrations of other growth factors with VEGF being the common pathway of neovascularization and progression to GBM.

Animals↗

PubMed2005

VEGF function in vascular pathogenesis.

Vascular endothelial growth factor (VEGF) has proven to be the most critical angiogenic factor identified to date; its discovery has transformed the field of angiogenesis research. After two decades of intense studies by numerous laboratories, the complex biology of VEGF is slowly being elucidated. VEGF is a collection of several different isoforms with overlapping but also unique functions. Furthermore, there are at least four different VEGF receptors, adding to the complexity of the VEGF/receptor system. VEGF exerts its effects on endothelial cells, inflammatory cells and neuronal cells, and its expression may contribute to the pathologies of diseases ranging from retinopathies to cancer. This review focuses on the biochemistry and cell biology of VEGF, with particular emphasis on the different isoforms and receptors, thereby illustrating the multifunctional nature of this growth factor. Lastly, critical considerations based on the complex biology of VEGF for developing specific and more targeted anti-VEGF therapeutic agents will be discussed.

Angiogenesis Inhibitors↗

PubMed1993

Recombinant fibroblast growth factor-1 promotes intimal hyperplasia and angiogenesis in arteries in vivo.

The prototype members of the heparin-binding fibroblast growth factor (FGF) family, acidic FGF (FGF-1) and basic FGF (FGF-2), are among the growth factors that act directly on vascular cells to induce endothelial cell growth and angiogenesis. In vivo, the role of the FGF prototypes in vascular pathology has been difficult to determine. We report here the introduction, by direct gene transfer into porcine arteries, of a eukaryotic expression vector encoding a secreted form of FGF-1. This somatic transgenic model defines gene function in the arterial wall in vivo. FGF-1 expression induced intimal thickening in porcine arteries 21 days after gene transfer, in contrast to control arteries transduced with an Escherichia coli beta-galactosidase gene. Where there was substantial intimal hyperplasia, neocapillary formation was detected in the expanded intima. These findings suggest that FGF-1 induces intimal hyperplasia in the arterial wall in vivo and, through its ability to stimulate angiogenesis in the neointima, FGF-1 could stimulate neovascularization of atherosclerotic plaques. Potentially, gene transfer of FGF-1 could also be used as a genetic intervention to improve blood flow to ischaemic tissues in selected clinical settings.

Animals↗

PubMed1996

[Breast carcinoma and breast saving therapy--a critical comment from the viewpoint of the pathologist].

The pathologist's contribution to decision-making for or against breast conserving treatment is based on his examination of the specimen from primary tumour surgery. First-line criteria for the assessment of the specimen are completeness, contour and versus plurifocal/multicentric spread), intracanalicular tumour components, lymphangiosis and haemangiosis. Second-line criteria are the histological and cytological grade of malignancy, preconditions for breast conserving treatment are favorable in consolidated in situ carcinomas up to 25 mm in diameter and in unifocal invasive carcinomas up to stage pT2 with low grade malignancy and without additional intraductal spread or angiosis. Breast conserving treatment is not indicated for multifocal or pT4 carcinomas and for carcinomas with extensive intraductal components or angiosis. When considering an unselected group of breast cancer patients, the pathological anatomic preconditions for breast conserving treatment will be very favourable in one-quarter of the cases. This approach will be feasible with limitations only in another one-fourth of the cases, whereas in about 50% of the patients, breast conserving treatment is dubious or should be rejected.

Biomarkers, Tumor↗

PubMed1995

[Pathology of wound healing].

In this review the morphologically defined steps of wound healing are described. Then the mechanisms of molecular regulation are discussed, which are the basis of the phases of wound healing. A main topic is the role of signal peptides in the regulation of cellular and stromal alterations during wound healing. An overview is given about the respective growth factors, their main function during wound healing and their receptors. Finally, analogies with fetal wound healing and the therapeutic modulation of wound-healing disturbances are discussed.

Animals↗

PubMed2005

[Comparison of power Doppler technique, microscopic examination and VEGF levels for the assessment of adrenal tumors vascularization].

The purpose of this study was to investigate the clinical usefulness of the color Doppler vascularity index (CDVI) in patients with adrenal masses before surgery. Twenty-four patients with adrenal masses were examined. The correlation between CDVI and microvessel density (MVD), vascular endothelial growth factor (VEGF) level and clinico-pathological factors was studied. There was a significant correlation between CDVI and VEGF level. The CDVI did not correlate with MVD. The CDVI was significantly higher in the patients with malignant or hormonally active tumors than in patients with benign non-hyperfunctioning lesions. Thus, the CDVI may be helpful in qualifying patients for adrenalectomy.

Adrenal Gland Neoplasms↗

PubMed2004

Angiostatin inhibits experimental liver fibrosis in mice.

BACKGROUND AND AIMS: Liver fibrosis is a response to chronic hepatic damage, which ultimately leads to liver failure and necessitates liver transplantation. A characteristic of fibrosis is pathological vessel growth. This type of angiogenesis may contribute to the disturbance of hepatocyte perfusion dynamics and lead to aggravation of disease. We hypothesized that angiostatin can inhibit pathological vessel growth and, consequently, the development of hepatic fibrosis. METHODS: Hepatic fibrosis was induced by injection of carbon tetrachloride for 5 weeks. Angiostatin mice received carbon tetrachloride for 5 weeks and angiostatin during weeks 4 and 5. After 5 weeks, immunohistochemistry for endothelial cell marker von Willebrand factor and for cell proliferation was performed. Angiogenesis was quantified by counting the number of immunopositive microvessels. Also, the relative fibrotic surface was determined using Sirius Red histostaining and computer image analysis. RESULTS: Immunohistochemistry revealed increased expression for von Willebrand factor in fibrotic livers. Immunopositive microvessels were localized in fibrotic areas surrounding larger vessels and in emerging fibrotic septa. Angiostatin reduced the number of immunopositive microvessels by 69% (p<0.001). In addition, angiostatin reduced the relative fibrotic area in the liver by 63+/-0.1% (p<0.001). Finally, angiostatin treatment was not associated with differences in cell proliferation. CONCLUSIONS: Angiostatin inhibits the development of pathological angiogenesis and liver fibrosis in mice. These results warrant further evaluation of angiostatin as an antifibrotic agent, potentially contributing to the deferment of liver transplantation and reduced recurrence of fibrotic disease in the transplanted liver.

Angiogenesis Inhibitors↗

PubMed2006

Prognostic significance of vascular endothelial growth factor expression and microvessel density in esophageal squamous cell carcinoma: comparison with positron emission tomography.

BACKGROUND: This study investigated whether the expression of vascular endothelial growth factor (VEGF) in a primary tumor and the intratumoral microvessel density (MVD) were independent prognostic factors in patients with an esophageal squamous cell carcinoma (SCC) in comparison with positron emission tomography (PET) by using (18)F-fluorodeoxyglucose (FDG) and stage. METHODS: Fifty-one patients with a newly diagnosed esophageal SCC who underwent preoperative FDG-PET and esophagectomy with intent to cure were enrolled in this study. The VEGF expression level, the intratumoral MVD, and the Ki-67 labeling index were evaluated by using immunohistochemical staining. Only significant variables in the univariate survival analysis were examined by multivariate survival analysis with the Cox proportional hazards model. RESULT: Cancer-related deaths occurred in 17 of 51 patients during the follow-up. Univariate survival analysis showed that the pathologic stage, pNM, maximum standardized uptake value of the primary tumor, tumor length on PET, number of PET-positive lymph nodes, PET stage, Ki-67 labeling index, intratumoral MVD, and the presence of VEGF expression were significant prognostic predictors for the overall survival. Multivariate analysis revealed that the pathologic stage, number of PET-positive nodes (0, 1, 2, or > or = 3), intratumoral MVD (cutoff, 60/mm(2)), and presence of VEGF expression were independent significant prognostic predictors for overall survival. CONCLUSION: In addition to the pathologic stage, the intratumoral MVD, the presence of VEGF expression, and the number of FDG-PET-positive nodes were independent prognostic predictors in patients with an esophageal SCC undergoing curative surgery.

Adult↗

PubMed2004

Diagnostic and therapeutic applications of recombinant antibodies: targeting the extra-domain B of fibronectin, a marker of tumor angiogenesis.

Angiogenesis, the sprouting of new blood vessels from preexisting ones, is a phenomenon associated to several human pathologies, including different potentially blinding ocular disorders, rheumatoid arthritis, and cancer. Indeed, ongoing angiogenesis is a characteristic feature of the majority of aggressive solid tumors, and is also a pre-requisite for the progression towards the metastatic phenotype. One established marker of angiogenesis is represented by an isoform of the oncofoetal fibronectin (FN), containing an additional domain inserted by alternative splicing of the FN pre-mRNA and called extra-domain B (ED-B). This isoform has been found to be present almost exclusively in the modified extra-cellular matrix surrounding newly-formed blood vessels in tumors (and other animal models of ocular pathologies), being completely absent from the normal vasculature in adult organs. This article reviews the recombinant antibodies raised against ED-B and the different methodologies used for the generation of these antibodies. Moreover, new diagnostic and therapeutic applications based on the delivery of bioactive molecules to tumor blood vessels by means of ED-B targeting will be discussed.

Animals↗