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PubMed1996

Histologic observation of continuity of transmural microvessels between the perigraft vessels and flow surface microostia in a porous vascular prosthesis.

To ascertain the histologic relationship between flow surface microostia and perigraft vessels in the healing of a porous vascular prosthesis, a series of careful histologic examinations were carried out on a preclotted, knitted Dacron graft, 8 mm in diameter and 7 cm long, after implantation in the canine infrarenal abdominal aorta for 3 months. Four adjacent longitudinal tissue blocks were taken from the middle for evaluation by means of light microscopy, scanning electron microscopy, transmission electron microscopy, and immunocytochemical staining, and the remainder of the specimen was stained with silver nitrate to allow visualization of microostia and cell borders on the flow surface. Following identification of two microostia adjacent to the area where samples had been taken for general healing evaluation, a 3 x 8 mm full-thickness block containing the microostia was embedded in glycol methacrylate and stained with hematoxylin and eosin. Of 240 serial sections cut from this block, 80 were prepared and examined. Silver staining revealed 42 microostia on the flow surface. Light, scanning, and transmission electron microscopy with endothelial factor VIII/von Willebrand factor stain confirmed a single layer of endothelial cells on the flow surface, and beneath was a well-organized neointima containing fusiform cells confirmed as smooth muscle by alpha-actin stain. Light microscopy of the serial sections revealed transmural microvessels, lined with endothelium, extending continuously between the flow surface ostia and the perigraft vessels in this porous vascular prosthesis.

Animals↗
PubMed2004

Angiogenesis and organ transplantation.

Angiogenesis is a vessel development process that maintains the vascular supply for organ function. Regulation of angiogenesis is provided by positive factors, such as vascular endothelial or basic fibroblast growth factors, and negative factors, such as thrombospondin and macrophage-derived inflammatory cytokines. While the role of angiogenesis in the wound healing, embryogenesis, tumor growth and proliferative diseases is clear, in organ transplantation it is not yet well established. Herein we discuss the potential role of angiogenesis in chronic renal disease and in transplant settings.

Angiopoietins↗
PubMed2002

Angiogenesis in non-small cell lung cancer. A new target for therapy.

Non-small cell lung cancer (NSCLC) is cured with surgery in a minority of affected persons. Chemotherapy and radiation can palliate and extend survival of patients with disease not amenable to surgery. Consequently, new treatment options are urgently needed. In the era of molecularly targeted therapeutics, the recent direction in cancer research has been to identify and modulate specific events in tumorigenesis. Angiogenesis, or new vessel formation, is one such event elucidated to be fundamental to the development, growth, and metastasis of cancers and is one of the characteristics that differentiates tumor from host. Thus, targeting of tumor neovasculature continues to generate tremendous enthusiasm and effort in drug development. Extensive research into the role of angiogenesis in NSCLC has produced a host of novel targets; their potential inhibitors, now numbering over 40, are in various phases of clinical testing around the world. The current lead compounds include inhibitors of matrix metalloproteinases, angiogenic growth factors and their receptor tyrosine kinases. Despite their impressive activity in animal models, definitive evidence of their antitumor activity in humans is yet to be established. We face several challenges as we look to advance the field of antiangiogenesis for the treatment of cancer, namely, the need for a better understanding of the optimal timing and dosing of antiangiogenic agents, the validation of imaging and quantification methods of tumor angiogenesis, and a new clinical trials design for a more expedient evaluation of novel cytostatic target modulators.

Angiogenesis Inducing Agents↗
PubMed1997

Organogenesis and angiogenin.

Our search for an angiogenesis-inducing factor in culture medium conditioned by human colon adenocarcinoma cells (HT-29) was inspired by the 'organizer' hypothesis originally postulated by Spemann. It led us to the isolation of angiogenin, a 14 kD protein homologous to pancreatic ribonuclease and one of the most potent stimulators of blood vessel formation known. This review summarizes the properties of angiogenin, its enzymatic and three-dimensional relationship to ribonuclease A (RNase A), those aspects of its structure that are critical for its biological function, and the therapeutic potential of angiogenin inhibition. Despite having the same arrangement of catalytic residues as RNase A, angiogenin has very low enzymatic activity. It lacks one of the four disulphide loops of RNase A; instead, the corresponding residues form part of a cell binding region. Both the catalytic activity and cell binding site are essential for angiogenesis. Angiogenin binds to cell-surface actin in confluent endothelial cells and to an as yet uncharacterized receptor on proliferating cells. Internalization and translocation to the nucleolus are also required for activity. Inhibitors of angiogenin can block angiogenesis in vitro and prevent tumour growth in vivo. Thus, a noncytotoxic neutralizing monoclonal antibody prevents the establishment of HT-29 human tumour xenografts in up to 65% of treated athymic mice. In those tumours that develop, the number of vascular elements is reduced. Actin also prevents the establishment of tumours while exhibiting no toxic effects at daily doses > 50 times the molar amount of circulating mouse angiogenin. These antagonists also inhibit the appearance of tumours derived from two other human tumour cell lines. Inhibition of the action of angiogenin may prove to be an effective therapeutic approach for the treatment of malignant disease.

Angiogenesis Inducing Agents↗
PubMed2002

Enhanced fetoplacental angiogenesis in pre-gestational diabetes mellitus: the extra growth is exclusively longitudinal and not accompanied by microvascular remodelling.

AIMS/HYPOTHESIS: Morphometric studies on pregnancies complicated by gestational diabetes mellitus have found no evidence of increased fetoplacental angiogenesis. Here, placentas from control subjects and patients with pre-gestational Type I (insulin-dependent) diabetes mellitus were used to test for differences in measures of angiogenesis and vascular remodelling. METHODS: Term placentas were collected from non-diabetic subjects and well-controlled diabetic patients grouped according to duration and severity into White classes B, C, D and F/R. Tissues were obtained by uniform random sampling for position and orientation. Volumes, surface areas and lengths of peripheral villi and their capillaries were estimated stereologically. Comparisons were drawn by analysis of variance and used to interpret mechanisms of growth, villous capillarization and vessel remodelling. RESULTS: Placentas associated with all classes of diabetes contained greater (19-45%) volumes of fetal capillaries attributable solely to increases in the combined length of capillaries (12-47%) and not to alteration of vessel cross-sectional area or perimeter. Longitudinal growth tended to increase capillarization (capillary:villus length ratios up to 19% larger) but changes were inconsistent between diabetic classes. There was no evidence of altered vascular remodelling (cross-sectional shape factors, perimeter(2)/area, were preserved). CONCLUSIONS/INTERPRETATIONS: In well-controlled pre-gestational diabetes, fetoplacental angiogenesis is enhanced and occurs exclusively by longitudinal growth. Differences may involve hypoxic or other metabolic effects on endothelial cells, perivascular cells and angiogenic factors. The findings differ from those previously reported in gestational diabetes. No differences were associated exclusively with the presence of diabetic complications.

Age of Onset↗
PubMed2004

Nerve growth factor supplementation reverses the impairment, induced by Type 1 diabetes, of hindlimb post-ischaemic recovery in mice.

AIMS/HYPOTHESIS: Type 1 diabetes increases the risk of peripheral ischaemia and impairs recovery once ischaemia occurs, probably because the healing process is hampered by diabetes-induced endothelial dysfunction. In normoglycaemic mice subjected to limb ischaemia, blockade of nerve growth factor (NGF) compromises reparative angiogenesis. In the present study, we evaluated if expressional alterations of endogenous NGF system components are associated with diabetes-related impairment in neovascularisation. In addition, we tested whether the correction of NGF liabilities benefits post-ischaemic healing of Type 1 diabetic animals. METHODS: Unilateral hindlimb ischaemia was produced in streptozotocin-induced Type 1 diabetic mice. Purified murine NGF (20 microg daily for 14 days) or PBS were injected into ischaemic adductors. Non-diabetic mice given PBS served as controls. Hindlimb blood flow was analysed sequentially for up to 14 days. At necroscopy, adductors were removed for quantification of microvessel density, endothelial cell apoptosis and NGF receptor expression. NGF content was determined by ELISA three days after ischaemia. In vitro, we tested whether NGF protects endothelial cells from apoptosis induced by high glucose and whether vascular endothelial growth factor-A (VEGF-A) is involved in this beneficial effect. RESULTS: Muscles removed from Type 1 diabetic mice showed reduced NGF content and up-regulation of the NGF p75 receptor. NGF supplementation promoted capillarisation and arteriogenesis, reduced apoptosis, and accelerated blood flow recovery. NGF stimulated VEGF-A production by human endothelial cells incubated in high-glucose medium and conferred resistance against high-glucose-induced apoptosis via a VEGF-A-mediated mechanism. CONCLUSIONS/INTERPRETATION: NGF protects endothelial cells from apoptosis induced by Type 1 diabetes and facilitates reparative neovascularisation. The findings may open up new therapeutic options for the treatment of diabetic complications.

Animals↗
PubMed2002

The role of angiogenesis in prostate development and the pathogenesis of prostate cancer.

New vessel formation, a highly-regulated, active process commencing in the embryo and evident notably during the pubertal growth spurt, is essential for normal prostate development. Reactivation of this process in response to physiological stimuli, particularly hypoxia in mature tissues, occurs with new vessels forming principally from stromal components. Although angiogenesis is complex, putatively involving a multitude of angiogenic factors and inhibitors, there is powerful evidence of the importance of the VEGF system in the development of both the normal prostate and prostate cancer. Recent advances include an understanding of how castration acts through the VEGF system to inhibit angiogenesis. Stromal-endothelial and epithelial-endothelial interactions are just beginning to be investigated. A better understanding of how physiological angiogenesis is controlled should help to provide further insights into the mechanism of disregulated angiogenesis in tumours. Ultimately, new antiangiogenic agents are likely to find a role in the management of patients with prostate cancer.

Animals↗
PubMed2001

Mathematical modeling of the onset of capillary formation initiating angiogenesis.

It is well accepted that neo-vascular formation can be divided into three main stages (which may be overlapping): (1) changes within the existing vessel, (2) formation of a new channel, (3) maturation of the new vessel. In this paper we present a new approach to angiogenesis, based on the theory of reinforced random walks, coupled with a Michaelis-Menten type mechanism which views the endothelial cell receptors as the catalyst for transforming angiogenic factor into proteolytic enzyme in order to model the first stage. In this model, a single layer of endothelial cells is separated by a vascular wall from an extracellular tissue matrix. A coupled system of ordinary and partial differential equations is derived which, in the presence of an angiogenic agent, predicts the aggregation of the endothelial cells and the collapse of the vascular lamina, opening a passage into the extracellular matrix. We refer to this as the onset of vascular sprouting. Some biological evidence for the correctness of our model is indicated by the formation of teats in utero. Further evidence for the correctness of the model is given by its prediction that endothelial cells will line the nascent capillary at the onset of capillary angiogenesis.

Angiogenesis Inducing Agents↗
PubMed1999

Do cerebral arteriovenous malformations recur after angiographically confirmed total extirpation?

Cerebral arteriovenous malformations (AVMs) are thought to result from a failure of embryogenesis in the otherwise normal differentiation of primordial vascular channels into mature arteries, capillaries, and veins. Although these are essentially congenital vascular malformations, marked enlargement and/or recurrence of cerebral AVMs has been reported in the recent literature. Using MEDLINE (1966- 1998), we searched the recurrence of cerebral AVMs and analyzed all reported recurrent cases after total surgical extirpation and negative postoperative angiogram, and discussed the proposed mechanisms of the recurrence of cerebral AVMs. A thorough literature survey disclosed only 12 documented recurrent cases (9 were documented in English and 3 in Japanese), which shows the rarity of the recurrence of cerebral AVMs, although the actual rate of recurrence is not known because of the lack of routine long-term follow-up. The location of recurrent cerebral AVMs was the cerebral hemisphere, and initial presentation was hemorrhage in all cases. Recurrence occurred in patients under 20 years of age in 9 of 11 cases, which implies the propensity of recurrence of cerebral AVMs in immature brain vasculature. There are no definite proven mechanisms to explain why congenital anomalies such as cerebral AVMs recur after total extirpation, but recently two plausible mechanisms have been proposed. One is angiogenesis disregulated by vas-cular endothelial growth factor (VEGF) and the other is a new anatomical entity, 'hidden compart-ments'. Although VEGF is one of the main angiogenetic factors and its important role in fetal brain and pathological neovascularization has been reported, the synthesis of VEGF might be insufficient to explain the recurrence of cerebral AVMs because VEGF-positive staining is also found in nonrecurrent patients. Hidden compartments are angiographically unfilled compartments, in spite of an adequate examination, which may be located within, contiguous with, or relatively far from the angiographically demonstrated AVM. Although it might explain unsolved clinical phenomena such as regrowth, recurrence, and per- or postoperative unanticipated bleeding and brain swelling, the existence of hidden compartments should be proved by high-resolution radiological examinations or during operations. The presence of recurrent cerebral AVMs after complete extirpation by modern microsurgical techniques indicates that cerebral angiography in the early postoperative stage, the golden standard to assess the disappearance of cerebral AVMs, is not sufficient to eliminate the risk of hemorrhage, and careful long-term follow-up studies should be planned.

Journal Article↗
PubMed2003

[Angiogenesis research--quo vadis?].

The field of angiogenesis research has seen an explosion of knowledge within the last 10 years. More than 3500 angiogenesis-related papers are presently being published per year compared to the less than 200 annual papers published in the early 1990s. Paralleling the progress in the field of basic angiogenesis research, translational research has led to the identification of more than 100 angiomanipulatory compounds. Presently, more than 40 substances are in various phases of clinical trials. The prospect of these exciting developments is presently dampened by the negative outcome of some advanced clinical trials. Thus, following euphoria and disillusion, the field is presently experiencing that translational clinical research requires endurance to eventually accomplish the successful implementation of angiomanipulatory therapies in the clinical setting. The present article provides an overview of the field of angiogenesis research and summarizes ongoing efforts aimed at developing angiomanipulatory therapies.

Adult↗
PubMed2004

A priori implantation potential does not differ in eutopic endometrium of patients with and without endometriosis.

BACKGROUND: In endometriosis, angiogenesis is a crucial step for implantation of the exfoliates. A priori potential to induce angiogenesis by vascular endothelial growth factor (VEGF) expression was compared in eutopic endometrium of patients with and without endometriosis to discriminate the pivotal pathogenic step that differs in endometriosis. METHODS: In an experimental prospective study, endometrium samples were obtained from endometriosis patients (n=10) and from healthy, ovulating women as controls (n=6) undergoing curettage and laparoscopy for benign gynaecological conditions at the Aachen University Hospital, Aachen, Germany. Endometrial fragments were transplanted to the chicken chorioallantoic membrane (CAM) and re-explanted after 0, 24, 48, 72 and 96 h of cultivation for analysis. The main outcome measure was VEGF mRNA expression and protein localisation in endometrial fragments as parameters of angiogenic induction that was quantified by the vessel index. RESULTS: VEGF mRNA expression increased significantly in endometrial fragments of endometriosis and control patients (p<0.05). Protein is expressed in the glands and endometrial stroma. The vessel index is significantly elevated compared with native CAM controls. Endometrial fragments of endometriosis and control patients showed no significant differences in VEGF expression or angiogenic induction. CONCLUSIONS: Eutopic endometrial fragments of patients with and without endometriosis do not differ in their VEGF expression or angiogenic activity in the CAM assay. Implantation is obviously decided by external regulating influences on the exfoliates.

Animals↗
PubMed2003

Role of hypoxia in tumor angiogenesis-molecular and cellular angiogenic crosstalk.

The mechanisms by which tumors recruit their vasculature has been subject to intense investigations. The acquisition of a functional blood supply seems to be rate-limiting for the ability of a tumor to grow beyond a certain size and to metastasize to other sites. Accumulating evidence indicates that hypoxia and the key transcriptional system, HIF (hypoxia-inducible factor), are the major triggers for new blood vessel growth in malignant tumors. Although vessel growth and maturation are complex and highly coordinated processes requiring the sequential activation of a multitude of factors, there is a consensus that vascular endothelial growth factor and angiopoietin signaling represent crucial steps in tumor angiogenesis. Recent insights into cellular and molecular crosstalk suggest a model in which hypoxia, HIF, and several HIF target genes participate in the coordinated collaboration between tumor, endothelial, inflammatory/hematopoietic, and circulating endothelial precursor cells to enhance and promote tumor vascularization. A well-integrated understanding of this intricate microenvironment may offer new opportunities for therapeutic intervention.

Angiopoietins↗
PubMed2003

EphB receptors and ephrinB ligands: regulators of vascular assembly and homeostasis.

Eph receptors comprise the largest family of receptor tyrosine kinases consisting of eight EphA receptors (with five corresponding glycosyl-phosphatidyl-inositol-anchored ephrinA ligands) and six EphB receptors (with three corresponding transmembrane ephrinB ligands). Originally identified as neuronal pathfinding molecules, genetic loss of function experiments have identified EphB receptors and ephrinB ligands as crucial regulators of vascular assembly, orchestrating arteriovenous differentiation and boundary formation. Despite these clearly defined rate-limiting roles of the EphB/ephrinB system for developmental angiogenesis, the mechanisms of the functions of EphB receptors and ephrinB ligands in the cells of the vascular system are poorly understood. Moreover, little evidence can be found in the recent literature regarding complementary EphB and ephrinB expression patterns that occur in the vascular system and that may bring cells into juxtapositional contact to allow bi-directional signaling between neighboring cells. This review summarizes the current knowledge of the role of EphB receptors and ephrinB ligands during embryonic vascular assembly and discusses recent findings on EphB/ephrinB-mediated cellular functions pointing to the crucial role of the Eph/ephrin system in controlling vascular homeostasis in the adult.

Animals↗
PubMed2005

Angiogenesis in normal and neoplastic ovaries.

Ovarian physiology is intricately connected to hormonally regulated angiogenic response. Recent advances in the post genomic revolution have significantly impacted our understanding of ovarian function. In an angiogenesis perspective, the ovary offers a unique opportunity to unravel the molecular orchestration of blood vessel development and regression under normal conditions. A majority of ovarian cancers develop from the single layer of epithelium surrounding the ovaries. Angiogenesis is critical for the development of ovarian cancer and its peritoneal dissemination. The present review summarizes recent findings on the angiogenic response in neoplastic ovaries and discusses the prospects of using anti-angiogenic approaches to treat ovarian cancer.

Angiogenesis Inducing Agents↗
PubMed2005

Sex steroid regulation of angiogenesis in breast tissue.

Angiogenesis is essential for normal function in the female reproductive tract and a prerequisite for growth and metastasis of solid tumors. Several factors, both inducers and inhibitors, play essential roles in the regulation of the angiogenic process. Exposure to sex steroids increases the risk of breast cancer but the mechanisms are poorly understood and the importance of angiogenesis in breast carcinogenesis is undefined. In the female reproductive tract ovarian hormones tightly regulate angiogenesis. The breast is also a target organ for sex steroids but very little is known about sex steroid effects on angiogenesis in normal breast tissue and breast cancer. In this review several regulators of angiogenesis, and their relation to sex steroids, in breast tissue are discussed. Increased knowledge in this area is of utmost importance for future therapeutic treatment options and for breast cancer prevention.

Angiogenesis Inducing Agents↗
PubMed2006

Antiangiogenic effect of 2-benzoyl-phenoxy acetamide in EAT cell is mediated by HIF-1alpha and down regulation of VEGF of in-vivo.

Benzophenones and its analogues are known for wide range of biological properties. Synthetic benzophenone analogue 2-benzoyl -phenoxy acetamide (BP-1) is proven to be potent antitumor and proapoptotic activity against EAT cells in-vivo. In the present report, we studied the antiangiogenic effect of BP-1 in EAT cells induced angiogenesis. Treatment with BP-1 in-vivo was demonstrated by the down regulation of the secretion of VEGF from EAT cells and inhibition of blood vessels formation indicating the potential angioinhibitory effect of BP-1 in EAT cells. HIF-1alpha protein, a transcription factor known to be key a regulator in hypoxia-induced angiogenesis was also down regulated by BP-1. Our findings indicated that, HIF-1alpha nuclear sequestration is repressed by BP-1 through inhibition of nuclear translocation. We postulate that diminished HIF-1alpha nuclear presence and activity in BP-1 treated EAT cells could be responsible for decreased VEGF expression and antiangiogenic effects.

Acetamides↗
PubMed2001

Plaque angiogenesis and atherosclerosis.

Therapeutic angiogenesis trials refer to the stimulation of collateral arterioles and new vascular conduits to perfuse ischemic myocardium and limbs. Atherosclerotic lesions responsible for vascular occlusions themselves are associated with angiogenesis within the vessel wall. Plaque neovascularization is comprised of a network of capillaries that arise from the adventitial vasa vasorum and extend into the intimal layer of atherosclerotic lesions and other types of vascular injury. The functions of these plaque capillaries are proposed to be important regulators of plaque growth and lesion instability. The development of agents that are positive and negative regulators of angiogenesis may have potential therapeutic implications in the progression and acute manifestations of atherosclerosis. This review focuses on the role of plaque angiogenesis in atherosclerosis and discusses the potential therapeutic applications of angiogenesis inhibitors in this disease.

Angiogenesis Inhibitors↗
PubMed2005

Critical role of microenvironmental factors in angiogenesis.

Therapeutic angiogenesis, which entails the induction of new blood vessels by the delivery of angiogenic growth factors, is a highly attractive approach to the treatment of ischemic diseases. However, it is becoming increasingly clear that this is not easily achieved, as the effects of angiogenic growth factors can differ markedly depending on the timing of their expression, on the shape of the concentration gradients they form in vivo, and the inter-actions between endothelial cells and pericytes they induce. In fact, the same dose of vascular endothelial growth factor can induce stable, nonleaky, pericyte-covered normal capillaries or aberrant vascular structures that develop into hemangiomas. This difference in outcome can be due solely to the spatial characteristics of the delivery method. If delivery allows a homogeneous spatial distribution of VEGF in the microenvironment around each producing cell, angiogenesis can be therapeutic, whereas if the total dose is the average of diverse spatial levels, aberrant angiogenesis cannot be avoided. To achieve therapeutic angiogenesis, a means of regulating the microenvironmental levels of angiogenic factors will be critical to the generation of effective new treatment strategies.

Animals↗