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Results for “Neovascularization, Pathologic”

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PubMed2005

[Clinical research on relationship between angiogensis and TCM syndrome type of cyclomastopathy].

OBJECTIVE: To study the relationship between angiogensis and TCM Syndrome type of cyclomastopathy (CMP) to investigate the objective standardization of TCM Syndrome diagnosis of the disease. METHODS: One hundred and forty patients with CMP were divided into three groups according to TCM syndrome typing. The pathological type, grade and expressions of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and microvascular density (MVD) in mammary biopsy were observed. RESULTS: The expressions of VEGF, bFGF and MVD was different in CMP patients of different TCM types and pathological grades (P < 0.05). The proportion of atypical proliferation, the count of MVD and the expression of VEGF and bFGF were higher in patients of phlegm and stasis type than those in Gan stagnation caused Qistagnation type and Chong and Ren meridians disorder type. CONCLUSION: TCM Syndrome type of CMP patients is related with vascular activity and grade of angiogensis. The pathological characteristics of mammary tissue and expression of VEGF, bFGF and MVD can be regarded as the objective indexes of TCM typing and clinical efficacy evaluation for CMP.

Adult↗

PubMed1996

Enhanced nitric oxide production induced by the administration of L-arginine does not inhibit arterial neointimal formation after overwhelming alloimmune injury.

BACKGROUND: Nitric oxide suppresses proliferation and function of T cells and inhibits proliferation of smooth muscle cells in vitro and in vivo. The purpose of this study was to determine whether nitric oxide, stimulated by means of the oral administration of L-arginine, would reduce the degree of intimal thickening produced by immune injury in rat arterial allografts. METHODS: Orthotopic femoral artery transplantation was done with Brown Norway donors and Lewis recipients. Seven days before operation, and for 39 additional days, one group received 2.25% L-arginine and one group received 0.01% N-omega-nitro-L-arginine in tap water; one group received tap water only. Forty days after operation, all arterial segments were excised and examined by histopathologic, morphometric, and immunohistochemical assays. RESULTS: There was no difference in the rejection response or degree of intimal thickening among the three groups. There were no qualitative differences in numbers of T cells, macrophages, or smooth muscle cells in the neointima, media, or adventitia among the untreated and treated groups. Induced nitric oxide synthase was present in the media and adventitia of the allograft vessels, but not in native rat arteries. CONCLUSIONS: Enhanced production of nitric oxide, via the administration of L-arginine, has been shown to reduce tissue pathologic changes in models of mechanical or dietary injury. Enhanced nitric oxide production did not suppress rejection or inhibit intimal thickening in this model of immune-mediated injury.

Administration, Oral↗

PubMed2002

Kinetics of integrin expression in the mouse model of proliferative retinopathy and success of secondary intervention with cyclic RGD peptides.

AIMS/HYPOTHESIS: Vitronectin-receptor-type integrins (alpha(v) beta(3) and alpha(v) beta(5)) are thought to be involved in the selective ablation of tumorigenic and other pathologic angiogenesis. Specifically, it has been shown that ligation inhibition of the alpha(v)-type integrins with cyclic penta-peptid peptide inhibits proliferative retinopathy by almost 80 % in a hypoxia-induced mouse model. METHODS: On the basis of growth factor and integrin expression dynamics in this model, secondary intervention approaches with cyclic RGDfV peptide were investigated. RESULTS: alpha(v)-integrin expression started immediately after induction of hypoxia (at postnatal day 12, p12) and persisted only during the initial period of neovascularization (until day p14). Vascular endothelial growth factor (VEGF) expression started at high values immediately after return of the mice into room air, and dropped rapidly to low values beyond day 13. In contrast, basic fibroblast growth factor (bFGF) was predominantly expressed during the phase of maximum angiogenesis which was noted between day p17 and 19. Based on these findings, cyclic penta peptide was administered subcutaneously at varying doses (2-20 microg/kg/day) for 5 days beginning either at day p14 (early intervention) or at day p17 (late intervention). Early secondary intervention showed a dose-dependent reduction of new vessels with maximum inhibition of 57 % (control 68.08 +/- 3.21 nuclei/section compared with RGDfV-treated 29.35 +/- 2.39 nuclei/section; p < 0.0001), whereas late secondary intervention had no effect. CONCLUSION/HYPOTHESIS: These data indicate that angiogenesis-related alpha(v)-integrin expression is VEGF- rather than bFGF-dependent, and the efficacy of cyclic penta-peptid (RGDfV)-treatment in proliferative retinopathy is only effective as long as the alpha(v)-integrin target is prominently expressed.

Animals↗

PubMed2006

Intracellular signaling in tumor and endothelial cells: The expected and, yet again, the unexpected.

In this issue of Cancer Cell, Phung and coworkers demonstrate that sustained endothelial activation of Akt by expression of constitutively activated Akt1 (myrAkt1) leads to blood vessels that essentially recapitulate the complex structural and functional abnormalities of tumor vessels. The authors provide evidence that rapamycin inhibition of PI3K/Akt/mTOR signaling in endothelial cells (ECs), by either reducing Akt activity or blocking mTOR, reverses the pathologic effects associated with excess VEGF signaling in the tumor vasculature. However, unexpected findings following mTOR inhibition in vivo highlight the seemingly paradoxical and complex effects of rapamycin on various cell types within the tumor microenvironment.

Antibiotics, Antineoplastic↗

PubMed2002

Bone marrow-derived stem cells target retinal astrocytes and can promote or inhibit retinal angiogenesis.

Adult bone marrow (BM) contains cells capable of differentiating along hematopoietic (Lin(+)) or non-hematopoietic (Lin(-)) lineages. Lin(-) hematopoietic stem cells (HSCs) have recently been shown to contain a population of endothelial precursor cells (EPCs) capable of forming blood vessels. Here we show that intravitreally injected Lin(-) BM cells selectively target retinal astrocytes, cells that serve as a template for both developmental and injury-associated retinal angiogenesis. When Lin(-) BM cells were injected into neonatal mouse eyes, they extensively and stably incorporated into forming retinal vasculature. When EPC-enriched HSCs were injected into the eyes of neonatal rd/rd mice, whose vasculature ordinarily degenerates with age, they rescued and maintained a normal vasculature. In contrast, normal retinal angiogenesis was inhibited when EPCs expressing a potent angiostatic protein were injected. We have demonstrated that Lin(-) BM cells and astrocytes specifically interact with one another during normal angiogenesis and pathological vascular degeneration in the retina. Selective targeting with Lin(-) HSC may be a useful therapeutic approach for the treatment of many ocular diseases.

Animals↗

PubMed2005

Rad GTPase attenuates vascular lesion formation by inhibition of vascular smooth muscle cell migration.

BACKGROUND: Rad (Ras associated with diabetes) GTPase is a prototypic member of a new subfamily of Ras-related GTPases with unique structural features, although its physiological role remains largely unknown. In the present study, we characterized the Rad function in vascular smooth muscle cells (VSMCs) and the influence of adenovirus-mediated Rad (Ad-Rad) gene delivery on vascular remodeling after experimental angioplasty. METHODS AND RESULTS: We documented for the first time that neointimal formation using balloon-injured rat carotid arteries was associated with a significant increase in Rad expression as determined by immunohistochemistry and quantitative real-time reverse-transcriptase polymerase chain reaction. The levels of Rad expression in VSMCs were highly induced by platelet-derived growth factor and tumor necrosis factor-alpha. Morphometric analyses 14 days after injury revealed significantly diminished neointimal formation in the Ad-Rad-treated carotid arteries compared with Ad-GFP or PBS controls, whereas the mutated form of Rad GTPase, which can bind GDP but not GTP, increased neointimal formation. Overexpression of Rad significantly inhibited the attachment and migration of VSMCs. In addition, Rad expression dramatically reduced the formation of focal contacts and stress fibers in VSMCs by blocking the Rho/ROK signaling pathway. CONCLUSIONS: Our data clearly identified Rad GTPase as a novel and critical mediator that inhibits vascular lesion formation. Manipulation of the Rad signaling pathway may provide new therapeutic approaches that will limit vascular pathological remodeling.

Actins↗

PubMed2003

[The clinical significance of angiogenesis in the bone marrow of acute leukemia patients].

OBJECTIVE: To study the angiogenesis in bone marrow and the level of vascular endothelial growth factor (VEGF) in bone marrow fluid from acute leukemia (AL) patients and to explore their clinical significance. METHODS: Microvessels in each bone marrow specimen section were counted by immunohistochemical identification of microvascular endothelial cells with anti-human von Willebrand factor under light microscopy in field 400 times. The VEGF level in bone marrow fluid was measured by ELISA. RESULTS: Microvessel counts in untreated AL patients (22.82/x 400 field) were significantly higher than those in normal controls (7.17/x 400 field) and in the bone marrow remission (BMR) AL patients (8.57/x 400 field) (P < 0.001, both), while the controls in the latter were higher than those in controls (P < 0.05). There was no difference in microvessel counts between untreated AL patients and relapse/refractory AL patients (21.83/x 400 field) (P > 0.05). In the untreated AL group, the microvessel counts showed difference neither between 23 ALL patients (23.09/x 400 field) and 43 ANLL patients (22.37/x 400 field) (P > 0.05), nor between patients with M(1 - 3) (22.91/x 400 field) and M(4 - 5) (21.46/x 400 field) the two subtypes of FAB (P > 0.05). There was a positive correlation between the microvessel counts and the percentage of blast cells in the bone marrow (r = 0.311, P < 0.01). The VEGF level in the bone marrow fluid in untreated AL patients (188.88 ng/L) was significantly higher than that in BMR AL patients (78.74 ng/L) and controls (79.52 ng/L) (P < 0.01), while the latter two groups had no difference between each other (P > 0.05). The VEGF level in the bone marrow fluid from ANLL group (270.12 ng/L) was enhanced significantly compared with that from ALL group (101.70 ng/L) (P < 0.01) and associated with the microvessel counts (r = 0.464, P < 0.05). CONCLUSION: Microvessel counts increased in the bone marrow in patients with different types of AL, suggesting that angiogenesis might play an important role in the pathology of AL. Testing the VEGF level in the bone marrow fluid from ANLL patients could reflect the degree of angiogenesis and disease condition.

Acute Disease↗

PubMed2003

[Angiogenic proteins: possible markers of physiopathological processes during fetal development].

Pregnancy involves the coordinated formation of new vessels, a process known as angiogenesis. Several growth factors and specific receptors, e.g. vascular endothelial growth factor (VEGF), PlGF (placenta growth factor) and the soluble VEGF-1 receptor (VEGFR-1) play essential roles in the process. Pregnancy-related pathological conditions (preeclampsia and intrauterine growth restriction (IUGR)) are associated with aberrant expressions of these molecules, which can be measured in blood fractions from pregnant women. Using these as markers before a clinical diagnosis is evident, seems feasible. Pathological conditions, such as inflammation and cancer, also induce angiogenesis. Measurements of other endothelium-derived molecules may add to the specificity and sensitivity of angiogenic proteins as markers.

Angiogenesis Inducing Agents↗

PubMed2004

Tumor angiogenesis in the bone marrow of multiple myeloma patients and its alteration by thalidomide treatment.

Angiogenesis in solid tumors is important to tumor growth, invasion and metastasis. Recently, it has been suggested that angiogenesis plays a certain role in the development of hematopoietic malignancies, including leukemia and multiple myeloma. We evaluated tumor angiogenesis in the bone marrow (BM) of multiple myeloma (MM) patients by calculating microvessel density (MVD) in needle-biopsy specimens obtained from 51 cases of untreated MM or monoclonal gammopathy of undetermined significance (MGUS). The MVD in the BM of donors for transplantation and patients with non-hematological diseases was calculated as a control. There was an obvious increase in MVD in the BM of MM patients, and the MVD correlated with the grade of myeloma cell invasion of the BM in the untreated MM cases. It was recently reported that thalidomide might be effective for the treatment of MM. We assessed the effect of thalidomide on angiogenesis in BM treatment of 11 patients with refractory MM. The concentration of M-protein in the serum or urine of seven of the 11 patients was reduced by at least 30% after thalidomide treatment, and MVD in the BM decreased in three of these seven cases in response to thalidomide. Increased plasma concentrations of basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) were observed in all 11 cases before thalidomide administration and both levels were reduced after treatment with thalidomide. Augmented angiogenesis in the bone marrow of MM patients was confirmed in the present study. It seems that thalidomide is effective in the treatment of MM through the impairment of angiogenesis by decreasing FGF-2 and VEGF production. This is the first report on pathological evidence in the bone marrow of MM before and after thalidomide treatment, in Japan.

Adult↗

PubMed2002

Expression of angiopoietin-1, angiopoietin-2, and Tie2 genes in normal ovary with corpus luteum and in ovarian cancer.

OBJECTIVE: The recent discovery of angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) has provided novel and important insights into the molecular mechanisms of blood vessel formation. Ang1 and Ang2 bind with similar affinity to the endothelial cell tyrosine kinase receptor Tie2. Our purpose was to assess the potential role of the Ang/Tie2 system in physiological and pathological angiogenesis in the ovary. METHODS: Ang1, Ang2, and Tie2 gene expression in 14 normal ovaries with corpus luteum (CL) and in 19 cases of ovarian cancer were analyzed by polymerase chain reaction of RNA after reverse transcription. The level of each gene expression was presented by the relative yield of each gene to the beta(2)-microglobulin gene, respectively. Furthermore, cellular distribution of Ang1 and Ang2 mRNA was examined by in situ hybridization, and localization of Tie2 was studied by immunochemistry. RESULTS: The Ang1, Ang2, and Tie2 gene expression in normal ovary with CL ranged from 0.18 to 1.06 (median 0.54), 0.31-2.64 (median 1.01), and 0.10-0.47 (median 0.20), respectively. The expression of these same genes in ovarian cancer ranged from 0.06 to 0.75 (median 0.14), 0.69-1.59 (median 1.12), and 0.04-0.35 (median 0.15), respectively. Ang1 gene expression in normal ovary with CL was significantly higher than that in ovarian cancer (p = 0.0004). The gene expression levels of Ang2 and Tie2 were statistically the same in both groups. There was a significant correlation between Ang1 gene expression and Tie2 gene expression in normal ovary with CL (r = 0.619, p = 0.018). No such significant correlation was found in ovarian cancer. Moreover, Ang2 gene expression showed no significant correlation with the Tie2 gene expression either in normal ovary with CL or in ovarian cancer. Transcripts for Ang1 were observed in CL cells and endothelial cells around CL, and in tumor cells and endothelial cells at the periphery of tumor invasion. Ang2 transcripts were expressed in the same patterns. Tie2 expression was positive primarily in the endothelial cells around CL and in those at the periphery of tumor invasion. CONCLUSION: Our results indicate that there is a difference in the Ang/Tie2 gene expression between physiological and pathological angiogenesis in the ovary. This finding may aid in the development of new therapeutic interventions for ovarian cancer.

Adult↗

PubMed1999

[Modulation of angiogenesis. A new therapeutic tool for vascular diseases].

Angiogenesis permits the growth of new vessels. This process may be modified during the course of some pathological phenomenon, i.e. cancer, atherosclerosis or diabetes. After a brief description of angiogenesis pathophysiology, the therapeutic possibilities in cardiovascular diseases are discussed. Initial results of therapeutic trials in coronary and peripheral artery diseases are detailed, and perspectives for the future are reviewed.

Arteriosclerosis Obliterans↗

PubMed2004

Idiopathic interstitial pneumonias: progress in classification, diagnosis, pathogenesis and management.

The idiopathic interstitial pneumonias are a heterogeneous group of poorly understood diseases with often devastating consequences for those afflicted. Subclassification of the idiopathic interstitial pneumonia based on clinical-radiological-pathological criteria has highlighted important pathogenic, therapeutic and prognostic implications. The most critical distinction is the presence of usual interstitial pneumonia, the histopathological pattern seen in idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis has a worse response to therapy and prognosis. New insight into the pathophysiology of usual interstitial pneumonia suggests a distinctly fibroproliferative process, and antifibrotic therapies show promise. While the clinical and radiographic diagnosis of idiopathic interstitial pneumonias can be made confidently in some cases, many patients require surgical lung biopsy to determine their underlying histopathology. A structured, clinical-radiological-pathological approach to the diagnosis of the idiopathic interstitial pneumonias, with particular attention to the identification of idiopathic pulmonary fibrosis, insures proper therapy, enhances prognostication, and allows for further investigation of therapies aimed at distinct pathophysiology.

Basement Membrane↗

PubMed1992

Quantitative image analysis of angiogenesis in rats implanted with a fibrin gel chamber.

Angiogenesis, a fundamental process in various physiological and pathological events, is generally studied using in vivo models, such as the chick chorioallantoic membrane or the rabbit cornea, which are difficult to quantitate. We developed the quantitation of angiogenesis in an in vivo model previously described by Dvorak et al [6]. Perforated plexiglass chambers filled with human or rat fibrin were implanted into the dorsal subcutaneous space of a Wistar rat. After four days of implantation, a sequentially organized invasion of the fibrin gel by various blood cell types occurred through the holes and neovascularized granulation tissue buds appeared. These buds presented mature neovessels and a new collagen matrix. Three dimensional computer image analysis of the chambers was performed using macroscopic and microscopic parameters: total vascularized area, bud height and equivalent diameter, number of vessels per bud and percentage of central vessels. The time course of the angiogenic response to rat or human fibrin gel was studied and 14 days was found to be the optimum period of implantation. The bud height and number of neovessels were not found to be significantly different when rat or human fibrin gels were used. This quantitative study was a prerequisite for further investigations of the effects of biological and pharmacological agents on angiogenesis.

Animals↗

PubMed2005

Antiangiogenesis in cancer therapy--endostatin and its mechanisms of action.

The first angiogenesis inhibitors for cancer have now been approved by the F.D.A. in the U.S. and in 28 other countries, including China. The majority of these are monotherapies that block VEGF. However, mutant tumor cells may over time produce redundant angiogenic factors. Therefore, for long-term use in cancer, combinations of angiogenesis inhibitors or broad spectrum angiogenesis inhibitors will be needed. The two most broad spectrum and least toxic angiogenesis inhibitors are Caplostatin and endostatin. Endostatin inhibits 65 different tumor types and modifies 12% of the human genome to downregulate pathological angiogenesis without side-effects. The recent discovery that small increases in circulating endostatin can suppress tumor growth and that orally available small molecules can increase endostatin in the plasma suggests the possible development of a new pharmaceutical field.

Angiogenesis Inhibitors↗

PubMed1998

Molecular biological changes in bladder cancer.

A large number of potential molecular markers of bladder cancer have been identified, although only a few are truly independent prognostic factors. A number of markers may need to be measured in a single tumour and used as a combination for use in the diagnosis and prognosis of transitional cell carcinoma (TCC). Epidermal growth factor receptor immunoreactivity has been shown to be an independent predictor of survival and stage progression. TP53 may be an independent predictor of recurrence and overall survival in TCC confined to the bladder, and TP53 alterations may predict chemosensitivity in patients who have had TCC treated by radical cystectomy. At present molecular techniques such as fluorescence in situ hybridization and the polymerase chain reaction are restricted to the laboratory, but immunohistochemical methods are available in most hospital pathology departments. There are some discrepancies and conflicting reports of the usefulness of molecular markers in different studies, and these need to be addressed in large, prospective, multi-institutional studies using standardized molecular techniques.

Animals↗

PubMed2001

Selective induction of neuropilin-1 by vascular endothelial growth factor (VEGF): a mechanism contributing to VEGF-induced angiogenesis.

Neuropilin (NRP) 1, previously identified as a neuronal receptor that mediates repulsive growth cone guidance, has been shown recently to function also in endothelial cells as an isoform-specific receptor for vascular endothelial growth factor (VEGF)(165) and as a coreceptor in vitro of VEGF receptor 2. However, its potential role in pathologic angiogenesis remains unknown. In the present study, we first show that VEGF selectively up-regulates NRP1 but not NRP2 via the VEGF receptor 2-dependent pathway. By NRP1 binding analysis, we showed that its induction by VEGF accompanies functional receptor expression. Endothelial proliferation stimulated by VEGF(165) was inhibited significantly by antibody perturbation of NRP1. In a murine model of VEGF-dependent angioproliferative retinopathy, intense NRP1 mRNA expression was observed in the newly formed vessels. Furthermore, selective NRP1 inhibition in this model suppressed neovascular formation substantially. These results suggest that VEGF cannot only activate endothelial cells directly but also can contribute to robust angiogenesis in vivo by a mechanism that involves up-regulation of its cognate receptor expression.

Animals↗

PubMed2002

Autologous transplantation of genetically modified iris pigment epithelial cells: a promising concept for the treatment of age-related macular degeneration and other disorders of the eye.

Age-related macular degeneration (ARMD) is the leading cause for visual impairment and blindness in the elder population. Laser photocoagulation, photodynamic therapy and excision of neovascular membranes have met with limited success. Submacular transplantation of autologous iris pigment epithelial (IPE) cells has been proposed to replace the damaged retinal pigment epithelium following surgical removal of the membranes. We tested our hypothesis that the subretinal transplantation of genetically modified autologous IPE cells expressing biological therapeutics might be a promising strategy for the treatment of ARMD and other retinal disorders. Pigment epithelium-derived factor (PEDF) has strong antiangiogenic and neuroprotective activities in the eye. Subretinal transplantation of PEDF expressing IPE cells inhibited pathological choroidal neovascularization in rat models of laser-induced rupture of Bruch's membrane and of oxygen induced ischemic retinopathy. PEDF expressing IPE transplants also increased the survival and preserved rhodopsin expression of photoreceptor cells in the RCS rat, a model of retinal degeneration. These findings suggest a promising concept for the treatment of ARMD and other retinal disorders.

Adenoviridae↗

PubMed2003

The pedicle artery sign based on sonography with color Doppler imaging can replace second-stage tests in women with abnormal vaginal bleeding.

OBJECTIVE: Unenhanced transvaginal sonography is not accurate in the detection of endometrial polyps. Currently, second-stage tests such as saline contrast sonohysterography and office hysteroscopy are used to diagnose endometrial lesions, but both have limitations and side effects. We proposed visualization of the pedicle artery on color Doppler imaging as a sign of polyps. METHODS: This was a prospective observational study involving 3099 consecutive patients referred for assessment of the endometrium and myometrium. The uterus was assessed in sagittal and coronal planes using color Doppler sonography. Patients with suspected endometrial pathology on sonography were noted and the volume of the focal lesion was calculated. Patients with a clearly visible pedicle artery reaching the central part of the endometrium were regarded as test-positive. The gold standard was defined as the presence or absence of an endometrial polyp at hysterectomy, hysteroscopy and/or endometrial histology on dilatation and curettage within 1 year of sonography. RESULTS: Of the 3099 women, no gold standard was available in 2230. Only 28 of the 199 patients who were test-positive did not have a gold standard. In the 869 patients in whom a gold standard was available, 182 had one or more endometrial polyps. The pedicle artery test had an apparent sensitivity for detection of endometrial polyps of 76.4%, specificity of 95.3%, positive predictive value (PPV) of 81.3%, and negative predictive value of 93.8%. When extending the test to the prediction of any focal intracavitary pathology the PPV was 94.2%. CONCLUSIONS: The pedicle artery test has a very high PPV for intracavitary pathology. We expect that in the majority of patients with an endometrial polyp this test may replace more invasive established second-stage tests, such as saline contrast sonohysterography and office hysteroscopy.

Adult↗