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PubMed2000

The detection and comparison of angiogenesis-associated factors in pyogenic granuloma by immunohistochemistry.

BACKGROUND: Pyogenic granuloma is a benign inflammatory lesion demonstrating obvious activity of angiogenesis. Female steroid hormones are believed to play important roles in the etiology because the lesion is frequently found in females with high levels of sex hormones. Few molecular mechanisms of the pathogenesis have been proposed and proven. The purpose of this study was to detect and compare the expression of angiogenesis-associated factors among healthy gingiva, gingiva from periodontitis, and pyogenic granuloma to clarify the pathogenesis of pyogenic granuloma. METHODS: Fifteen specimens were collected from each of 3 groups of gingiva (healthy gingiva, periodontitis, and pyogenic granuloma). The subjects were age and gender matched. The specimens were processed for immunohistochemistry to detect and compare the expression of 2 angiogenesis enhancers, i.e., vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), 2 angiogenesis inhibitors, i.e., angiostatin and thrombospondin-1 (TSP-1), and estrogen receptor (ER). Using the subject as the unit of statistical analysis, either analysis of variance or chi-square analysis was employed to show the statistically significant difference at a level P <0.05. RESULTS: The pyogenic granuloma group expressed significantly more VEGF and bFGF than healthy gingiva and periodontitis. The positive staining of VEGF was mostly localized in the cytoplasm of macrophages and fibroblasts while that of bFGF was in the extracellular matrix of lamina propria. Angiostatin was expressed significantly less in pyogenic granuloma than the other 2 groups and was mostly localized in the nuclei of endothelial cells and epithelial cells. There was no significant difference in the expression of TSP-1 and ER among the 3 groups. CONCLUSIONS: The results of this research suggest that the etiology of pyogenic granuloma is due to the imbalance between angiogenesis enhancers and inhibitors. Whether and how the angiogenesis-associated factors are regulated by female steroid hormones remain to be answered.

Adult↗
PubMed2004

Hyperglycemia-induced defects in angiogenesis in the chicken chorioallantoic membrane model.

Diabetes is associated with abnormal angiogenesis. Increased angiogenesis contributes to severe forms of diabetic retinopathy, but angiogenesis is decreased in response to myocardial ischemia in diabetic patients. We evaluated the direct effect of hyperglycemia on angiogenesis in the chicken chorioallantoic membrane assay, a model of active neoangiogenesis. Hyperglycemia, lasting up to 7 days, was induced in 7-day-old chick embryos by a single intravitellus glucose injection. Control embryos received either water (volumic control) or mannitol (osmotic control). Hyperglycemia decreased angiogenesis in this model from the 5th day on. The pattern and expression level of the main vascular growth factors' genes were not altered by hyperglycemia, as assessed by in situ hybridization and semiquantitative RT-PCR. As early as 2 days after hyperglycemia was induced, an increased apoptosis of endothelial cells and pericytes was detected by transferase-mediated deoxyuridine triphosphate nick-end labeling assay and electron microscopy. In the meantime, endothelial cell proliferation was decreased, as assessed by incorporation of bromo-deoxyuridine. Hyperglycemia can therefore impair angiogenesis without altering the expression level of vascular growth factors through induction of apoptosis and decreased proliferation of endothelial cells.

Allantois↗
PubMed2005

Impaired retinal angiogenesis in diabetes: role of advanced glycation end products and galectin-3.

Suppression of angiogenesis during diabetes is a recognized phenomenon but is less appreciated within the context of diabetic retinopathy. The current study has investigated regulation of retinal angiogenesis by diabetic serum and determined if advanced glycation end products (AGEs) could modulate this response, possibly via AGE-receptor interactions. A novel in vitro model of retinal angiogenesis was developed and the ability of diabetic sera to regulate this process was quantified. AGE-modified serum albumin was prepared according to a range of protocols, and these were also analyzed along with neutralization of the AGE receptors galectin-3 and RAGE. Retinal ischemia and neovascularization were also studied in a murine model of oxygen-induced proliferative retinopathy (OIR) in wild-type and galectin-3 knockout mice (gal3(-/-)) after perfusion of preformed AGEs. Serum from nondiabetic patients showed significantly more angiogenic potential than diabetic serum (P < 0.0001) and within the diabetic group, poor glycemic control resulted in more AGEs but less angiogenic potential than tight control (P < 0.01). AGE-modified albumin caused a dose-dependent inhibition of angiogenesis (P < 0.001), and AGE receptor neutralization significantly reversed the AGE-mediated suppression of angiogenesis (P < 0.01). AGE-treated wild-type mice showed a significant increase in inner retinal ischemia and a reduction in neovascularization compared with non-AGE controls (P < 0.001). However, ablation of galectin-3 abolished the AGE-mediated increase in retinal ischemia and restored the neovascular response to that seen in controls. The data suggest a significant suppression of angiogenesis by the retinal microvasculature during diabetes and implicate AGEs and AGE-receptor interactions in its causation.

Adult↗
PubMed2007

Type-2 diabetic Lepr(db/db) mice show a defective microvascular phenotype under basal conditions and an impaired response to angiogenesis gene therapy in the setting of limb ischemia.

Diabetes mellitus is associated with macro- and micro-angiopathy, leading to increased risk of peripheral ischemia. In the present study, we have characterized the microvascular phenotype at the level of limb muscles and the spontaneous angiogenesis response to surgically-induced unilateral limb ischemia in a murine model of type-2 diabetes, the obese C57BL/KsOlaHsd-Lepr(db/db) mice (Lepr(db/db)), and in non-diabetic heterozygous Lepr(db/+). Wild type C57BL mice (WT) were used as controls. The basal microvascular phenotype was determined in mice aged 3 or 5 months, while the response to limb ischemia was studied only in 5-month old mice. Moreover, in 5-month old ischemic Lepr(db/db) and Lepr(db/+), we have tested the therapeutic potential of local angiogenesis gene therapy with human tissue kallikrein (hTK) or constitutively-activated Akt kinase (Myr-Akt). We found that in the muscles of 3- or 5-month old Lepr(db/db), apoptosis of endothelial cells was enhanced and the densities of capillary and arteriole were reduced. Arterioles of Lepr(db/db) showed hypertrophic remodelling and, occasionally, lumen occlusion. Following ischemia, Lepr(db/db) showed a defective reparative angiogenesis in ischemic muscle, delayed blood flow recovery, and worsened clinical outcome as compared with controls. Five-month old Lepr(db/+) displayed an increase in endothelial cell apoptosis under basal conditions, while capillary and arteriole densities were normal. Lepr(db/+) mounted a proper reparative angiogenesis response to limb ischemia and regained blood flow to the ischemic limb, regularly. Local gene therapy with hTK or Myr-Akt induced angiogenesis in ischemic muscles of Lepr(db/+) and Lepr(db/db). However, in the Lepr(db/db) neither gene therapy approach improved the blood flow recovery and the clinical outcome from ischemia. In contrast, either hTK or Myr-Akt gene transfer improved the post-ischemic recovery of Lepr(db/+). Type-2 diabetes has a negative impact on the basal microvascular phenotype and severely impairs post-ischemic recovery of limb muscles. Gene therapy-induced stimulation of neovascularization might not suffice as a sole therapeutic strategy to combat type-2 diabetes-related vascular complications. In type-2 diabetic patients, therapeutic angiogenesis may need to be further optimized before being recommended for clinical applications.

Animals↗
PubMed1994

Formation of healing tissue and angiogenesis in repair of connective tissue stimulated by epidermal growth factor.

Epidermal growth factor (EGF) has been shown to stimulate connective tissue repair in the perforated mesentery of rats. The aim of the present investigation was to study the effect of EGF on the formation of healing tissue and angiogenesis in such repair. After laparotomy standardised perforations were made in the centre of the mesenteric "windows" with a scalpel. The rats were given intraperitoneal injections of either 10 micrograms EGF dissolved in phosphate-buffered saline (PBS), or PBS alone, twice daily for four consecutive days beginning on the day of operation. In the first experiment, healing tissue formation and angiogenesis was quantified morphometrically in perpendicularly cut mesenteric windows on days 1 to 10 after operation. Treatment with EGF caused the formation of significantly more healing tissue on days 2 to 7, but no stimulation of angiogenesis. In the second experiment, angiogenesis was quantified morphometrically on days 14 and 21. Mesenteric windows were spread out on objective slides after the capillary bed had been visualised by perfusion of carbon ink. Perforation caused a significant increase of microvascular density in the centre of the mesenteric windows on days 14 and 21. Treatment with EGF did not stimulate angiogenesis at any observation point. In conclusion, treatment with EGF significantly increased the formation of healing tissue in connective tissue repair in the perforated mesentery of rats, but did not affect angiogenesis.

Animals↗
PubMed2006

CCL2 regulates angiogenesis via activation of Ets-1 transcription factor.

Although recent studies have suggested that CC chemokine CCL2 may directly affect the angiogenesis, the signaling events involved in such regulation remain to be determined. This study investigated a potential signal mechanism involved in CCL2-induced angiogenesis. Our in vitro and in vivo (hemangioma model of angiogenesis) experiments confirmed earlier findings that CCL2 can induce angiogenesis directly. Using a gene array analysis, CCL2 was found to induce expression of several angiogenic factors in brain endothelial cells. Among the most prominent was an up-regulation in Ets-1 transcription factor. CCL2 induced a significant increase in Ets-1 mRNA and protein expression as well as Ets-1 DNA-binding activity. Importantly, Ets-1 antisense oligonucleotide markedly abrogated in vitro CCL2-induced angiogenesis, suggesting that Ets-1 is critically involved in this process. Activation of Ets-1 by CCL2 further regulated some of Ets-1 target molecules including beta(3) integrins. CCL2 induced significant up-regulation of beta(3) mRNA and protein expression, and this effect of CCL2 was prevented by the Ets-1 antisense oligonucleotide. The functional regulation of Ets-1 activity by CCL2 was dependent on ERK-1/2 cascade. Inhibition of ERK1/2 activity by PD98509 prevented CCL2-induced increases in Ets-1 DNA-binding activity and Ets-1 mRNA expression. Based on these findings, we suggest that Ets-1 transcription factor plays a critical role in CCL2 actions on brain endothelial cells and CCL2-induced angiogenesis.

Animals↗
PubMed2003

Hypoxia-induced angiogenesis during carcinogenesis.

The formation of new blood vessels, angiogenesis, is an essential process during development and disease. Angiogenesis is well known as a crucial step in tumor growth and progression. Angiogenesis is induced by hypoxic conditions and regulated by the hypoxia-inducible factor 1 (HIF-1). The expression of HIF-1 correlates with hypoxia-induced angiogenesis as a result of the induction of the major HIF-1 target gene, vascular endothelial cell growth factor (VEGF). In this review, a brief overview of the mechanism of angiogenesis is discussed, focusing on the regulatory processes of the HIF-1 transcription factor. HIF-1 consists of a constitutively expressed HIF-1 beta (HIF-1beta) subunit and an oxygen-regulated HIF-1 alpha (HIF-1a) subunit. The stability and activity of HIF-1alpha are regulated by the interaction with various proteins, such as pVHL, p53, and p300/CBP as well as by post-translational modifications, hydroxylation, acetylation, and phosphorylation. It was recently reported that HIF-1alpha binds a co-activator of the AP-1 transcription factor, Jab-1, which inhibits the p53-dependent degradation of HIF-1 and enhances the transcriptional activity of HIF-1 and the subsequent VEGF expression under hypoxic conditions. ARD1 acetylates HIF-1alpha and stimulates pVHL-mediated ubiquitination of HIF-1alpha. With a growing knowledge of the molecular mechanisms in this field, novel strategies to prevent tumor angiogenesis can be developed, and from these, new anticancer therapies may arise.

Animals↗
PubMed1992

Inhibition of angiogenesis by staurosporine, a potent protein kinase inhibitor.

The effect of staurosporine, a potent inhibitor of protein kinases, on embryonic angiogenesis was studied in an in vivo assay system involving chorioallantoic membranes of growing chick embryo. Staurosporine inhibited embryonic angiogenesis in a dose-related manner, the ID50 value being 71 pmol/egg. Staurosporine dose-dependently suppressed the proliferation of vascular endothelial cells, an important event involved in the angiogenesis process. The IC50 value was 0.88 nM. In contrast, staurosporine did not affect the migration of vascular endothelial cells. These results suggest that staurosporine affected embryonic angiogenesis probably by inhibiting endothelial cell proliferation. In addition, these results might support the notion that certain protein kinase(s) could be implicated in induction of angiogenesis and also that staurosporine would be a useful compound for studying a mode of action of angiogenesis occurring in various diseases, including tumor development.

Alkaloids↗
PubMedDate not supplied

Pathophysiology of tumor angiogenesis and its relevance in renal cell cancer.

In many cases, solid tumors exhibit numerous and highly permeable blood vessels. For a long time, this observation drew little attention. In the early 70's, however, Folkman proposed for the first time the potential relevance of tumor angiogenesis (formation of new vessels) for tumor growth and metastasis (6). He realized that tumors up to a diameter of 1-2 mm could be nurtured with oxygen and energy simply by diffusion (prevascular phase). Further growth, however, would require newly formed blood vessels. He hypothesized that (assuming the formation of new vessels was essential for tumor growth) pharmacological inhibition of angiogenesis could be developed as a new, more specific form of tumor treatment. In recent years, several groups have investigated the pathophysiology of tumor angiogenesis. Folkman's hypothesis that tumor growth is dependent on the formation of new vessels was supported by several experiments: Implants of different tumors into an avascular cornea initially have a slow growth rate that increases exponentially after infiltration of new vessels into the tumors (9). Inversely, the growth rate of solid tumors decreases with increasing distance to the supplying capillaries (27). The onset of neovascularization at the bases of human melanomas is directly associated with tumor growth and metastasis (25). Experiments with transgenic mice have demonstrated that the transition from hyperplastic to malignant cell growth occurs parallel to the onset of angiogenesis (7). Tumor vessel density has been shown to be associated with tumor progression and the clinical course in many human tumors (e.g. of the breast, lung, colon, cervix, prostate and bladder). Aside from the basic research on the formation of new (tumor) vessels, it is the therapeutic potential of various inhibitors of angiogenesis, some of which are currently tested in clinical (phase I/II) studies, that deserves special scientific attention. This review gives an overview of the relevance of angiogenesis for tumor growth, especially for renal cancers. It also discusses the potential advantages and disadvantages of different anti-angiogenic therapeutic approaches.

Animals↗
PubMed1999

Restoration of wild-type p16 down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human gliomas.

Recent studies have indicated that the loss of p16 is a frequent event in the progression of malignant gliomas. The loss of p16 promotes the acquisition of malignant characteristics in gliomas, which are among the most angiogenic of all human tumors. High-grade gliomas are distinguished from low-grade gliomas by intense angiogenesis in addition to their frequent loss of p16. New therapeutic strategies aimed at inhibiting tumor angiogenesis on the basis of molecular mechanisms are theoretically attractive. Here we evaluate the effect of p16 gene replacement on the angiogenesis of gliomas. Infection with a recombinant replication-defective adenovirus vector containing the cDNA of wild-type p16 significantly reduced the expression of vascular endothelial growth factor, which is thought to be a pivotal mediator of tumor angiogenesis, in p16-deleted glioma cells. Restoring wild-type p16 expression into p16-deleted glioma cells markedly inhibited angiogenesis induced by tumor cells in vivo. Furthermore, wild-type p16 inhibited neovascularization more potently than did wild-type p53 transfer. These findings indicate that the p16 gene plays an important role in the regulation of glioma angiogenesis, suggesting a novel function of the p16 gene.

Adenoviruses, Human↗
PubMed1999

UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice.

UFT, an anticancer agent that is composed of tegafur (FT) and uracil at a molar ratio of 1:4, is widely used in clinical practice in Japan to treat cancer patients requiring a long-term chemotherapy, and it is associated with few side effects, if any. In this study, we have evaluated the inhibitory effect of UFT against RENCA cell-induced angiogenesis by a dorsal air sac assay. Marked angiogenesis is induced by implantation of a chamber containing RENCA cells into mice. In this model, UFT showed a strong angiogenesis-inhibitory effect, whereas 5-fluorouracil (5-FU) and doxifluridine were less effective. Additional experiments revealed FT to be effective component of UFT; uracil remained ineffective in the inhibition of angiogenesis. Moreover, we have found that gamma-hydroxybutyric acid and gamma-butyrolactone, the metabolites of FT, possess a potent angiogenesis inhibitory effect that is amplified when the compounds are administered by a continuous infusion. This may reflect a transition in blood concentration of each metabolite resulting from the administration of UFT. Similar results were also obtained with respect to 5-FU. It was suggested that UFT has a stronger angiogenesis-inhibitory effect than did other fluorinated pyrimidines, partly due to its pharmacokinetic properties characterized by maintaining of higher and long-lasting blood levels of 5-FU and partly due the inhibitory effects derived from gamma-hydroxybutyric acid and gamma-butyrolactone, UFT-specific metabolites.

4-Butyrolactone↗
PubMed1999

Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors.

Tumor angiogenesis is mediated by tumor-secreted angiogenic growth factors that interact with their surface receptors expressed on endothelial cells. Vascular endothelial growth factor (VEGF) and its receptor [fetal liver kinase 1 (Flk-1)/kinase insert domain-containing receptor] play an important role in vascular permeability and tumor angiogenesis. Previously, we reported on the development of anti-Flk-1 and antikinase insert domain-containing receptor monoclonal antibodies (mAbs) that potently inhibit VEGF binding and receptor signaling. Here, we report the effect of anti-Flk-1 mAb (DC101) on angiogenesis and tumor growth. Angiogenesis in vivo was examined using a growth factor supplemented (basic fibroblast growth factor + VEGF) Matrigel plug and an alginate-encapsulated tumor cell (Lewis lung) assay in C57BL/6 mice. Systemic administration of DC101 every 3 days markedly reduced neovascularization of Matrigel plugs and tumor-containing alginate beads in a dose-dependent fashion. Histological analysis of Matrigel plugs showed reduced numbers of endothelial cells and vessel structures. Several mouse tumors and human tumor xenografts in athymic mice were used to examine the effect of anti-Flk-1 mAb treatment on tumor angiogenesis and growth. Anti-Flk-1 mAb treatment significantly suppressed the growth of primary murine Lewis lung, 4T1 mammary, and B16 melanoma tumors and growth of Lewis lung metastases. DC101 also completely inhibited the growth of established epidermoid, glioblastoma, pancreatic, and renal human tumor xenografts. Histological examination of anti-Flk-1 mAb-treated tumors showed evidence of decreased microvessel density, tumor cell apoptosis, decreased tumor cell proliferation, and extensive tumor necrosis. These findings support the conclusion that anti-Flk-1 mAb treatment inhibits tumor growth by suppression of tumor-induced neovascularization and demonstrate the potential for therapeutic application of anti-VEGF receptor antibody in the treatment of angiogenesis-dependent tumors.

Animals↗
PubMed2000

Do angiogenesis and growth factor expression predict prognosis of esophageal cancer?

A retrospective study of surgically resectable esophageal cancers was undertaken to determine the relationship between angiogenesis score and growth factor expression with tumor size, histology, degree of differentiation, depth of invasion, nodal disease, and the presence of Barrett's esophagus. The office and hospital charts of 27 patients who had esophageal resection for carcinoma between 1990 and 1995 at Rush-Presbyterian-St. Luke's Medical Center were reviewed. Data collection included patient demographics, survival, tumor size, histology, differentiation, depth of invasion, nodal metastases, and the presence of Barrett's esophagus. The pathology specimens were immunostained for von Willebrand factor (factor VIII-related antigen). Immunostaining was also performed for vascular endothelial growth factor and transforming growth factor alpha. Twenty normal esophageal specimens served as controls. Angiogenesis score was determined by counting vessels under conventional light microscopy at x200 magnification, and growth factor expression was graded on a scale of 1 to 4. Cancers had higher angiogenesis and growth factor expression than controls (P = 0.01). Patient age, tumor size, histology, differentiation, depth of invasion, and Barrett's esophagus did not correlate with angiogenesis score or tumor growth factor expression. Lymph node status did correlate with both angiogenesis score and growth factor expression (P < or = 0.02). We conclude that high angiogenesis score and growth factor expression correlate with the presence of lymph node metastases. This may help select patients for preoperative radiation and chemotherapy or determine the extent of surgery performed for esophageal carcinoma.

Adult↗
PubMed2000

Role of alpha v integrins during angiogenesis.

Angiogenesis depends on specific molecular interactions between vascular cells and components of the extracellular matrix. This review focuses on the recent advances in the understanding of the mechanism of action of integrins and integrin antagonists during angiogenesis. For example, angiogenesis induced with vascular endothelial growth/permeability factor but not with basic fibroblast growth factor (bFGF) depends on integrin avb5 and Src kinase activity. In contrast, bFGF-induced angiogenesis requires integrin avb3 and functions independently of Src. Recent studies document a role for integrins and growth factor regulation of Src family kinases during angiogenesis. We also discuss the effect of av integrin antagonists on angiogenesis during tumor growth, inflammatory disease, and retinopathy and summarize recent clinical progress in using av integrin antagonists.

Animals↗
PubMed2000

Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression.

Our recent studies (R. Pollock et al., Clin. Cancer Res., 4: 1985-1994, 1998; M. Milas et al., Cancer Gene Ther., in press, 2000) have shown that the restoration of wild-type (wt) p53 enhances cell cycle control in vitro and inhibits the growth of human soft-tissue sarcoma in severe combined immunodeficient mice. We hypothesized that the antitumor effect of wt p53 overexpression in sarcoma cells is attributable not only to enhanced cell cycle control but also to inhibition of angiogenesis. We evaluated the effect of restoring wt p53 function on angiogenesis in human soft-tissue sarcoma harboring mutant p53. Restoration of wt p53 expression in human leiomyosarcoma SKLMS-1 cells that contain mutant p53 markedly inhibited angiogenesis induced by tumor cells in vivo. Angiogenesis assays using an in vivo Matrigel plug assay demonstrated that less neovascularization in severe combined immunodeficient mice was observed with conditioned medium (CM) from human synovial sarcoma cells expressing wt p53 compared with CM from human synovial sarcoma cells expressing mutant p53. Microvessel density and microvessel counts were lower in tumor xenografts from cells containing wt p53 than in tumor xenografts from cells containing mutant p53. The growth and migration of murine lung endothelial cells were decreased when cells were treated with CM from sarcoma cells expressing wt p53 compared with CM from sarcoma cells expressing mutant p53. The introduction of wt p53 into sarcoma cells containing mutant p53 significantly reduced the expression of vascular endothelial growth factor (VEGF), which is a key mediator of tumor angiogenesis. Stimulation of endothelial cell migration by CM from cells expressing mutant p53 was significantly reduced after anti-VEGF neutralizing antibody was added to the CM. Using luciferase as the reporter of VEGF promoter activity, we found that wt p53 inhibited VEGF promoter activity in SKLMS-1 cells. Deletion analysis defined an 87-bp region (bp -135 to -48) in the VEGF promoter that is necessary for inhibiting VEGF promoter activity by wt p53. The transcription factor Sp1 may be involved in the repression of VEGF promoter activity by wt p53 in SKLMS-1 cells. These data indicated that wt p53 can suppress angiogenesis in human soft-tissue sarcomas by transcriptional repression of VEGF expression.

Animals↗
PubMed1999

Basic Concepts of (Myocardial) Angiogenesis: Role of Vascular Endothelial Growth Factor and Angiopoietin.

Blood vessels are essential for the supply of oxygen and nutrients to the heart. An imbalance between oxygen demand and supply (ischemia), as occurs when coronary arteries become obstructed by atherosclerotic plaques, triggers a response to improve myocardial perfusion by the formation of new capillaries (angiogenesis) and by the enlargement of preexisting collateral vessels (arteriogenesis). Recently, novel insights have been obtained in the molecular mechanisms of angiogenesis and in its control by hypoxia. This has lead to the design of strategies to improve myocardial perfusion. However, rational design of therapeutic angiogenesis mandates a better understanding of the molecular basis of angiogenesis. This review discusses the role of two prime classes of angiogenic molecules, namely of vascular endothelial growth factor (VEGF) and angiopoietin (Ang), and addresses novel insights in the regulation of angiogenesis by hypoxia. In addition, a novel mouse model of ischemic cardiomyopathy with signs of hibernation is presented. Possible implications for therapeutic myocardial angiogenesis are discussed.

Journal Article↗
PubMed2001

Angiogenesis induced by electrical stimulation is mediated by angiotensin II and VEGF.

OBJECTIVE: Physiological angiogenesis in skeletal muscle is an adaptive response to physical training and electrical stimulation. This study investigated the role of angiotensin II (Ang II) in regulating both angiogenesis and vascular endothelial growth factor (VEGF) protein expression induced by electrical stimulation. METHODS: The right tibialis anterior (TA) and extensor digitorum longus (EDL) muscles of Sprague-Dawley rats were stimulated for 8 hours per day for 7 days. The contralateral muscles served as controls. Two days before the surgery and throughout the stimulation protocol, the rats received either lisinopril or losartan in their drinking water. Rats without any drug treatment were used as control. Immunohistochemistry and Western blot analysis were performed to identify the source and quantify the VEGF protein expression in these muscles. The relationship between angiogenesis and VEGF expression was explored using a VEGF-neutralizing antibody. RESULTS: Chronic electrical stimulation of the skeletal muscles led to significant increases in vessel density (14% and 30% for EDL and TA, respectively) within 7 days. In addition, stimulation increased VEGF protein levels in the stimulated muscles. Both lisinopril and losartan blocked elevation in VEGF expression and inhibited the angiogenesis induced by stimulation. VEGF neutralization also inhibited angiogenesis, confirming the relationship between Ang II, VEGF, and vessel growth. CONCLUSION: The current study suggests a pathway involving angiotensin II receptors (AT1) and VEGF in electrically stimulated angiogenesis.

Angiotensin II↗
PubMed2001

Patterns of angiogenesis in nonsmall-cell lung carcinoma.

BACKGROUND: Tumor angiogenesis plays a pivotal role in tumor growth, maintenance, and metastasis. The objective of the current study was to evaluate the prognostic value of estimates of tumor angiogenesis and vascular endothelial growth factor (VEGF) status in 143 primary tumors from patients who underwent radical surgery for nonsmall-cell lung carcinoma (NSCLC). METHODS: Tumor sections were stained by immunohistochemistry for CD34 and VEGF. Angiogenesis was estimated both by a modification of the method described by Weidner and by the use of a 25-point Chalkley eyepiece graticule. VEGF intensity was evaluated semiquantitatively in three groups of patients. The vascular data were correlated with histopathologic tumor type and grade, TNM classification, patient age, and the endpoint (death). RESULTS: The estimates of vascular score did not reveal any prognostic information. In 35 patients (24%), invasive tumor growth was identified with a highly ordered alveolar microvessel pattern. In parallel sections, the intensity of VEGF staining was weak in tumors that exhibited an alveolar microvessel pattern only, and it was more intense in tumors that demonstrated a mixed alveolar and diffuse angiogenic pattern. The 35 patients with alveolar microvessel pattern had a significantly better survival (P = 0.007). In a Cox multivariate analysis, the results demonstrated an independent bad prognostic value of high disease stage (P < 0.0001), adenocarcinoma (P = 0.004), greater age (P = 0.01), and angiogenic microvessel pattern (P = 0.01). CONCLUSIONS: The authors believe that the alveolar vascular pattern represented preexisting alveolar vessels, that is, the alveoli were filled up by tumor cells that exploited the existing highly vascular bed of the lungs. Therefore, this subgroup was characterized by tumor progression without the induction of angiogenesis. The current data do not support a significant prognostic role for tumor angiogenesis in patients who are diagnosed with NSCLC. This may have implications for therapy aimed at inhibiting tumor growth by the inhibition of angiogenesis.

Adult↗