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Results for “Neovascularization, Pathologic”

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PubMed2003

Can we identify novel angiogenesis inhibitors from cultured embryonic cells?

The first vascular structures in embryos are formed by vasculogensis, the de novo formation of blood vessels from angioblasts. However, angiogenesis, the sprouting of capillaries from pre-existing blood vessels, are also involved in the development of embryonic vascular system in certain organs, such as the kidney or the brain. These facts led us to speculate that embryonic tissues could produce potent angiogenesis inhibitors as well to refine the primitive vascular development. In the present study, we found that two different types of cultured human embryonic cells, 293T and WI-38, produced soluble factors that completely inhibited angiogenic effects of vascular endothelial growth factor on microvascular endothelial cells. Since angiogenesis is related to various pathological states, including tumor growth and metastasis and diabetic retinopathy, to identify novel potent angiogenesis inhibitors from cultured embryonic cells by differential display techniques or DNA microarray technology might be a valuable strategy to develop a novel therapeutic approach.

Angiogenesis Inhibitors↗

PubMed2005

Review article: angiogenesis soluble factors as liver disease markers.

Angiogenesis is the formation of new blood vessels from pre-existing ones; it has been studied at the molecular level in different pathologies and is currently considered a promising novel therapeutic target in cancer. Recently, the use of angiogenesis soluble factors as markers of tumour growth has been investigated. The knowledge gained has led to test their use as therapeutic agents. Additionally, angiogenesis soluble factors could be used for the follow-up of pathologies that currently require monitoring with invasive techniques, like chronic viral hepatitis or renal and haematological diseases. The different factors have been described in multiple studies. In some cases, such as hepatocellular carcinoma, a potential use as prognostic markers has been suggested.

Angiogenesis Inducing Agents↗

PubMed1995

Selected histochemical and immunocytochemical markers of biological activity of brain blood vessels.

In the review dyes, enzymes and molecules were described, which serve as markers of various functions of blood vessels or their structural elements. From among histochemically revealed enzymes those were described which are of significance in the characteristics of the blood-brain barrier function. Attention has been paid to dyes with which pathology in blood vessel wall can be visualized. Among molecules, mainly adhesion and markers of angiogenesis were described. Their discovery is possible with the use of antibodies in immunohistochemical methods taking into account the accessibility to antibodies and their usefulness in the recognition of pathophysiological processes in the central nervous system.

Biomarkers↗

PubMed2005

Cyclin I is expressed in human breast cancer and closely associated with VEGF and KDR expression.

In the present study, cyclin I protein expression in 114 invasive human breast cancers was correlated with cell cycle and angiogenesis-related proteins and clinico-pathological data. A strong association was found between cytoplasmic cyclin I staining and VEGF (p = 0.001) as well as the VEGF receptor KDR (p = 0.001), suggesting a link between cyclin I and angiogenesis.

Amino Acid Sequence↗

PubMed2004

Selection of recombinant phages binding to pathological endothelial and tumor cells of rat glioblastoma by in-vivo display.

Pathological endothelial cells are attractive targets to selectively abrogate tumor growth. However, only a few cell surface molecules to address the endothelium of pathological blood vessels are known, but it could be anticipated that many more molecular addresses associated with abnormal endothelial function and proliferation could serve as potential candidates for development of drug delivery agents. To obtain a library of peptides mediating binding of recombinant M13 phages to endothelium of experimental rat brain tumors, in-vivo display of a combinatorial heptapeptide and a splenocyte M13 library was used. Phage clones were selected that bind to rat brain tumor endothelium in-vivo and phage proteins detected in tissues by immunohistochemistry. Some of the recombinant phages diffused or were transported far into the surrounding tumor tissue, where they persisted for several days. Sequence analysis of insertion peptides revealed surprising similarities to angiogenic and anti-angiogenic factors or matrix and guidance molecules that appear to be involved in glioblastoma pathology. In-vivo phage display of recombinant M13 phages is a tool to select peptides targeting pathological endothelium. Insertion peptides, their corresponding cellular proteins and ligands might have a variety of applications in providing molecular tools for targeting tumor vascular beds with diagnostic probes and therapeutic substances and might open new opportunities for treating frequently fatal glial tumors.

Animals↗

PubMed2004

The clinical relevance of adrenomedullin: a promising profile?

Adrenomedullin (AM) is a peptide that possesses potentially beneficial properties. Since the initial discovery of the peptide by Kitamura et al. in 1993, the literature has been awash with reports describing its novel mechanisms of action and huge potential as a therapeutic target. Strong evidence now exists that AM is able to act as an autocrine, paracrine, or endocrine mediator in a number of biologically significant functions, including the endothelial regulation of blood pressure, protection against organ damage in sepsis or hypoxia, and the control of blood volume through the regulation of thirst. Its early promise as a potential mediator/modulator of disease was not, however, entirely as a result of the discovery of physiological functions but due more to the observation of increasing levels measured in plasma in direct correlation with disease progression. In health, AM circulates at low picomolar concentrations in plasma in 2 forms, a mature 52-amino acid peptide and an immature 53-amino acid peptide. Plasma levels of AM have now been shown to be increased in a number of pathological states, including congestive heart failure, sepsis, essential hypertension, acute myocardial infarction, and renal impairment. These earliest associations have been further supplemented with evidence of a role for AM in other pathologies including, most intriguingly, cancer. In this review, we offer a timely review of our current knowledge on AM and give a detailed account of the putative role of AM in those clinical areas in which the best therapeutic opportunities might exist.

Adrenomedullin↗

PubMed2006

Epithelial damage and angiogenesis in the airways of children with asthma.

RATIONALE: Airway remodeling and inflammation are characteristic features of adult asthma that are still poorly investigated in childhood asthma. OBJECTIVES: To examine epithelial and vascular changes as well as the inflammatory response in airways of children with asthma. METHODS: We analyzed bronchial biopsies obtained from 44 children undergoing bronchoscopy for appropriate clinical indications other than asthma: 17 with mild/moderate asthma (aged 2-15 yr), 12 with atopy without asthma (1-11 yr), and 15 control children without atopy or asthma (1-14 yr). By histochemistry and immunohistochemistry, we quantified epithelial loss, basement membrane thickness, number of vessels, and inflammatory cells in subepithelium. RESULTS: Epithelial loss and basement membrane thickness were increased in children with asthma compared with control subjects (p = 0.005 and p = 0.0002, respectively) and atopic children (p = 0.002 and p = 0.005, respectively). The number of vessels and eosinophils was increased not only in asthmatic children (p = 0.03 and p = 0.0002, respectively) but also in atopic children without asthma (p = 0.03 and p = 0.008, respectively) compared with control subjects. When we stratified the analysis according to age, we observed that children with asthma younger than 6 yr had increased epithelial loss, basement membrane thickening, and eosinophilia compared with control subjects of the same age. CONCLUSIONS: Epithelial damage and basement membrane thickening, which are pathologic features characteristic of adult asthma, are present even in childhood asthma. Other changes, such as airway eosinophilia and angiogenesis, were also observed in atopic children without asthma. These observations suggest that pathologic changes occur early in the natural history of asthma and emphasize the concept that some of these lesions may characterize atopy even in the absence of asthmatic symptoms.

Adolescent↗

PubMed2006

Differential angiogenic regulation of experimental colitis.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the intestinal tract with unknown multifactorial etiology that, among other things, result in alteration and dysfunction of the intestinal microvasculature. Clinical observations of increased colon microvascular density during IBD have been made. However, there have been no reports investigating the physiological or pathological importance of angiogenic stimulation during the development of intestinal inflammation. Here we report that the dextran sodium sulfate and CD4+CD45RBhigh T-cell transfer models of colitis stimulate angiogenesis that results in increased blood vessel density concomitant with increased histopathology, suggesting that the neovasculature contributes to tissue damage during colitis. We also show that leukocyte infiltration is an obligatory requirement for the stimulation of angiogenesis. The angiogenic response during experimental colitis was differentially regulated in that the production of various angiogenic mediators was diverse between the two models with only a small group of molecules being similarly controlled. Importantly, treatment with the anti-angiogenic agent thalidomide or ATN-161 significantly reduced angiogenic activity and associated tissue histopathology during experimental colitis. Our findings identify a direct pathological link between angiogenesis and the development of experimental colitis, representing a novel therapeutic target for IBD.

Angiogenesis Inhibitors↗

PubMed2000

Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR imaging: correlation with histologic grade.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MR imaging may be used to quantify tissue fractional blood volume (fBV) and microvascular permeability. We tested this technique in patients with brain tumors to assess whether these measurements correlate with tumor histologic grade. METHODS: Twenty-two patients with newly diagnosed gliomas underwent MR imaging followed by surgery. Imaging consisted of one pre- and six dynamic postcontrast 3D spoiled gradient-recalled acquisition in the steady state data sets after administration of a single dose (0.1 mmol/kg) of contrast material. Signal intensity changes in blood and tissue were kinetically analyzed using a bidirectional two-compartment model, yielding estimates of fBV (mL/cm3) and microvascular permeability (mL/100 cm3 per minute). Stained tumor specimens were scored on a four-point scale (1 = low grade, 4 = high grade). RESULTS: Histologic examination revealed one grade 1, eight grade 2, seven grade 3, and six grade 4 tumors. fBV values ranged from 0.5% to 13.7%. Permeability values ranged from -0.4 to 18.8, with a strong correlation (r = 0.83) to tumor grade. Despite some overlap between the permeability values of specific tumors from different grades, differences in the mean were statistically significant. There was a weak correlation (r = 0.39) between estimated fBV and tumor grade, and no statistically significant difference among fBV values in any of the groups. CONCLUSION: This relatively simple method of analysis provides quantitative estimates of fBV and microvascular permeability in human brain tumors, with the permeability being predictive of pathologic grade. The technique can be easily implemented on clinical scanners and may prove useful in the assessment of tumor biology and in therapeutic trials.

Adult↗

PubMed2003

Hepatocyte growth factor/scatter factor can induce angiogenesis independently of vascular endothelial growth factor.

OBJECTIVE: Hepatocyte growth factor/scatter factor (HGF/SF) promotes vascular endothelial growth factor (VEGF) expression and induces angiogenesis in multiple pathological conditions. The present study was designed to delineate the HGF/SF and VEGF signaling cascades during angiogenesis by using PTK787, a selective VEGF receptor antagonist. METHODS AND RESULTS: PTK787 produced a concentration-dependent (10(-8) to 10(-6) mol/L) inhibition of VEGF-induced angiogenesis, without altering the basal or HGF/SF-induced response in vitro. In contrast, the nonspecific kinase inhibitor genistein blocked the HGF/SF-induced effect. Both VEGF and HGF/SF induced a rapid phosphorylation of extracellular receptor kinases-1 and -2 (ERKs) and Akt. PTK787 inhibited the VEGF-induced activation of Akt and ERKs, without affecting the HGF/SF-induced phosphorylation. Treatment with VEGF and HGF/SF increased total neovascularization in a murine scaffold granuloma model, but no additive or synergistic interactions were observed. PTK787 (50 mg/kg) blocked the VEGF-induced response without altering the basal or HGF/SF-induced neovascularization. CONCLUSIONS: We demonstrate that HGF/SF can induce angiogenesis independently of VEGF, possibly through the direct activation of the Akt and ERKs. These results demonstrate the necessity of a multitargeted approach for the rational design of newer therapies to inhibit pathophysiological angiogenesis.

Animals↗

PubMed2004

Development of new drugs in angiogenesis.

Angiogenesis, the growth of new capillaries from pre-existing vessels, contributes to the development and progression of a variety of physio-pathological conditions. There is growing evidence that anti-angiogenic drugs will improve future therapies of diseases like cancer, rheumatoid arthritis and ocular neovascularisation. Conversely, therapeutic angiogenesis is an important homeostatic response contributing to limit the damage to ischemic tissues. Molecular processes involved in angiogenesis include stimulation of endothelial growth by cytokine production (i.e. vascular endothelial growth factor, VEGF; fibroblast growth factor-2, FGF-2), degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs), and migration of endothelial cells mediated by integrins (cell membrane adhesion molecules). Drugs targeting pathologic angiogenesis have been designed to interfere with any of these steps and are currently undergoing evaluation in early clinical studies. Important therapeutic strategies are: suppression of activity and signaling pathways activated by the major angiogenic regulators like VEGF and FGF-2; inhibition of function of alphav-integrins and MMPs; exploitation of endogenous anti-angiogenic molecules like angiostatin and endostatin. The strategy to "silence" endothelium with antiangiogenic drugs to starve tumors, provides a novel approach for cancer treatment. The unique targets of these drugs (endothelium) make them distinct from traditional cytotoxic chemotherapeutic agents. Conversely, gene transfer of angiogenesis inducers is the new approach for therapeutic neovascularization, which is under investigation using a variety of growth factors and a wide array of potential delivery systems, including the application of the gene as naked DNA or by viral vector. The status of pro- and anti-angiogenic therapies is here presented and discussed.

Angiogenesis Inhibitors↗

PubMed2004

Peroxisome proliferator-activated receptor gamma ligands improve the antitumor efficacy of thrombospondin peptide ABT510.

An expanding capillary network is critical for several pathologic conditions. In cancer, the decrease of antiangiogenic thrombospondin-1 (TSP1) often enables an angiogenic switch, which can be reversed with exogenous TSP1 or its peptide derivative ABT510. TSP1 acts by inducing endothelial cell apoptosis via signaling cascade initiated at CD36, a TSP1 antiangiogenic receptor. Here, we show that the ligands of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), 15-deoxy-delta(12,14)-prostaglandin J2, troglitazone, and rosiglitazone increased PPARgamma and CD36 expression in endothelial cells and improved the efficacy of TSP1 and ABT510 in a CD36-dependent manner. The ABT510 and PPARgamma ligands cooperatively blocked angiogenic endothelial functions in vitro and neovascularization in vivo. In tumor xenografts, 15-deoxy-delta(12,14)-prostaglandin J2 and troglitazone synergistically improved antiangiogenic and antitumor effects of ABT510. Our data provide one mechanism for the in vivo angioinhibitory effect of PPARgamma ligands and show fine-tuning of the antiangiogenic efficacy via targeted up-regulation of the endothelial receptor.

Angiogenesis Inhibitors↗

PubMed2005

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis.

Fibroblast growth factors (FGFs) are a family of heparin-binding growth factors. FGFs exert their pro-angiogenic activity by interacting with various endothelial cell surface receptors, including tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins. Their activity is modulated by a variety of free and extracellular matrix-associated molecules. Also, the cross-talk among FGFs, vascular endothelial growth factors (VEGFs), and inflammatory cytokines/chemokines may play a role in the modulation of blood vessel growth in different pathological conditions, including cancer. Indeed, several experimental evidences point to a role for FGFs in tumor growth and angiogenesis. This review will focus on the relevance of the FGF/FGF receptor system in adult angiogenesis and its contribution to tumor vascularization.

Animals↗

PubMed2005

From angiogenesis to neuropathology.

Angiogenesis--the growth of new blood vessels--is a crucial force for shaping the nervous system and protecting it from disease. Recent advances have improved our understanding of how the brain and other tissues grow new blood vessels under normal and pathological conditions. Angiogenesis factors, especially vascular endothelial growth factor, are now known to have roles in the birth of new neurons (neurogenesis), the prevention or mitigation of neuronal injury (neuroprotection), and the pathogenesis of stroke, Alzheimer's disease and motor neuron disease. As our understanding of pathophysiology grows, these developments may point the way towards new molecular and cell-based therapies.

Animals↗

PubMed2006

From the design to the clinical application of thromboxane modulators.

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H(2) (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. In the first part of this review, we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part, we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock, preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis.

Animals↗

PubMed2001

Quantitative RT-PCR assay for mRNA of VEGF and histone H4 in the determination of proliferative and angiogenic activity in vulvar pathology.

Proliferative and angiogenic activity of tissue specimens taken from women with various vulvar pathologies were evaluated by determining the number of mRNA VEGF molecules and H4 histone mRNA molecules, by means of the QRT-PCR (TaqMan) technique. Following a cluster analysis the results, where normalised. Euclidean distances were used, all the cases were classified into three groups of pathologies. Group I included low degree vulvar pathologies, group II included high degree vulvar pathologies and group III included vulvar pathologies with high proliferative and angiogenic activity. Significant differences were found in the proliferative and angiogenic activity between groups I and III, and between groups II and III, while no statistically significant differences were found between groups I and II.

Carcinoma in Situ↗

PubMed2004

Role of nitric oxide in tumor angiogenesis.

Nitric oxide (NO) is an important signalling molecule that acts in many tissues to regulate different physiological and pathological processes. We have contributed to demonstrate that NO stimulates angiogenesis and mediates the effect of different angiogenic molecules. In human tumors NOS expression and activity correlate with tumor growth and aggressiveness, through angiogenesis stimulation and regulation of angiogenic factor expression. Drugs affecting the NOS pathway appear promising antitumor strategies by reducing edema, inhibiting angiogenesis and facilitating the delivery of chemotherapeutical agents.

Animals↗

PubMed2005

Imaging angiogenesis: applications and potential for drug development.

Recognition of the importance of angiogenesis to tumor growth and metastasis has led to efforts to develop new drugs that are targeted to angiogenic vasculature. Clinical trials of these agents are challenging, both because there is no agreed upon method of establishing the correct dosage for drugs whose mechanism of action is not primarily cytotoxic and because of the long time it takes to determine whether such drugs have a clinical effect. Therefore, there is a need for rapid and effective biomarkers to establish drug dosage and monitor clinical response. This review addresses the potential of imaging as a way to accurately and reliably assess changes in angiogenic vasculature in response to therapy. We describe the advantages and disadvantages of several imaging modalities, including positron emission tomography, x-ray computed tomography, magnetic resonance imaging, ultrasound, and optical imaging, for imaging angiogenic vasculature. We also discuss the analytic methods used to derive blood flow, blood volume, empirical semiquantitative hemodynamic parameters, and quantitative hemodynamic parameters from pharmacokinetic modeling. We examine the validity of these methods, citing studies that test correlations between data derived from imaging and data derived from other established methods, their reproducibility, and correlations between imaging-derived hemodynamic parameters and other pathologic indicators, such as microvessel density, pathology score, and disease outcome. Finally, we discuss which imaging methods are most likely to have the sensitivity and reliability required for monitoring responses to cancer therapy and describe ways in which imaging has been used in clinical trials to date.

Angiogenesis Inhibitors↗