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Results for “Neovascularization, Pathologic”

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PubMed2005

Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis.

The VEGF/VPF (vascular endothelial growth factor/vascular permeability factor) ligands and receptors are crucial regulators of vasculogenesis, angiogenesis, lymphangiogenesis and vascular permeability in vertebrates. VEGF-A, the prototype VEGF ligand, binds and activates two tyrosine kinase receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). VEGFR1, which occurs in transmembrane and soluble forms, negatively regulates vasculogenesis and angiogenesis during early embryogenesis, but it also acts as a positive regulator of angiogenesis and inflammatory responses, playing a role in several human diseases such as rheumatoid arthritis and cancer. The soluble VEGFR1 is overexpressed in placenta in preeclampsia patients. VEGFR2 has critical functions in physiological and pathological angiogenesis through distinct signal transduction pathways regulating proliferation and migration of endothelial cells. VEGFR3, a receptor for the lymphatic growth factors VEGF-C and VEGF-D, but not for VEGF-A, regulates vascular and lymphatic endothelial cell function during embryogenesis. Loss-of-function variants of VEGFR3 have been identified in lymphedema. Formation of tumor lymphatics may be stimulated by tumor-produced VEGF-C, allowing increased spread of tumor metastases through the lymphatics. Mapping the signaling system of these important receptors may provide the knowledge necessary to suppress specific signaling pathways in major human diseases.

Aging↗

PubMed2002

The role of fibroblast growth factors in vascular development.

Fibroblast growth factors (FGFs) are considered angiogenic factors, yet the exact relationship between FGF and vascular development in normal and pathological tissue has long remained elusive. However, recent results from gene inactivation and transgenic studies in mice and in culture systems have demonstrated the role of FGFs in vessel assembly and sprouting. FGFs also promote blood-vessel branching and induce lymphangiogenesis. Novel players in FGF-mediated angiogenesis have been identified, such as p38 mitogen-activated protein kinase. Tumour angiogenesis is regulated by FGFs directly or indirectly via secondary angiogenesis factors, such as vascular endothelial growth factor. The newly established angiogenic role of FGFs makes FGF or molecules targeting FGF and its receptor promising candidates for the development of novel therapeutics.

Animals↗

PubMedDate not supplied

[Chemokines, a new family of cytokines in inflammatory cell recruitment].

Cell recruitment is a crucial event in the establishment of both acute and chronic inflammatory responses, including acute and delayed type hypersensitivity reactions. Among other significant factors like adhesion molecules, chemokines and its receptors are crucial elements that lead leukocyte migration to the tissues. Chemokines are a large group of peptidic cytokines which have a conserved motif of 4 cisteins. These cistein residues form pairs which permit to classify them in two groups, the alpha and beta subfamilies. In general terms, alpha subfamily has preferential chemotactic activity on granulocytes, and beta subfamily attracts mainly lymphocytes and macrophages. Besides their chemotactic activity, chemokines also participate in some other important biological processes like hematopoiesis, angiogenesis, and anti-tumoral activity. Chemokines also play an important role in certain pathological conditions, for instance in some allergic processes they have an essential role in the pathogenesis. In autoimmune and infectious diseases, this cytokine family is also important as is suggested by the presence of chemokine receptors in rheumatoid arthritis inflammed synovia or the HIV receptor activity that chemokine receptors display which apparently play a significant role in the natural resistance against this infectious agent. Preferential leukocyte recruitment mediated by chemokines is a potential target for pharmacological modulation, which in turn may lead to a novel and efficient types of therapeutic control of inflammatory diseases with diverse etiology.

Animals↗

PubMed1996

Positive and negative regulation of angiogenesis: from cell biology to the clinic.

Virtually every subspecialty in medicine in one way or another deals with angiogenesis-associated physiological or pathological processes and, without exception, every organ system in the body has many diseases in which angiogenesis is an important component. This in itself makes the study of angiogenesis mandatory, in both basic science and clinical settings. Yet the study of angiogenesis does not require this justification. As a biological process it is extraordinarily rich, touching on virtually every aspect of modern cell biology, making it almost impossible for molecular biologists, biochemists and morphologists to ignore. Considerable therapeutic benefit can now be obtained through positive or negative manipulation of the angiogenic process, and this is due in large part to the rapid transfer to the clinical setting of knowledge acquired through a cell biological approach.

Animals↗

PubMed2000

Role of platelet-activating factor in cardiovascular pathophysiology.

Platelet-activating factor (PAF) is a phospholipid mediator that belongs to a family of biologically active, structurally related alkyl phosphoglycerides. PAF acts via a specific receptor that is coupled with a G protein, which activates a phosphatidylinositol-specific phospholipase C. In this review we focus on the aspects that are more relevant for the cell biology of the cardiovascular system. The in vitro studies provided evidence for a role of PAF both as intercellular and intracellular messenger involved in cell-to-cell communication. In the cardiovascular system, PAF may have a role in embryogenesis because it stimulates endothelial cell migration and angiogenesis and may affect cardiac function because it exhibits mechanical and electrophysiological actions on cardiomyocytes. Moreover, PAF may contribute to modulation of blood pressure mainly by affecting the renal vascular circulation. In pathological conditions, PAF has been involved in the hypotension and cardiac dysfunctions occurring in various cardiovascular stress situations such as cardiac anaphylaxis and hemorrhagic, traumatic, and septic shock syndromes. In addition, experimental studies indicate that PAF has a critical role in the development of myocardial ischemia-reperfusion injury. Indeed, PAF cooperates in the recruitment of leukocytes in inflamed tissue by promoting adhesion to the endothelium and extravascular transmigration of leukocytes. The finding that human heart can produce PAF, expresses PAF receptor, and is sensitive to the negative inotropic action of PAF suggests that this mediator may have a role also in human cardiovascular pathophysiology.

Anaphylaxis↗

PubMedDate not supplied

Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF).

Vascular endothelial growth factor (VEGF) was originally identified as an endothelial cell specific growth factor stimulating angiogenesis and vascular permeability. Some family members, VEGF C and D, are specifically involved in lymphangiogenesis. It now appears that VEGF also has autocrine functions acting as a survival factor for tumour cells protecting them from stresses such as hypoxia, chemotherapy and radiotherapy. The mechanisms of action of VEGF are still being investigated with emerging insights into overlapping pathways and cross-talk between other receptors such as the neuropilins which were not previously associated with angiogenesis. VEGF plays an important role in embryonic development and angiogenesis during wound healing and menstrual cycle in the healthy adult. VEGF is also important in a number of both malignant and non-malignant pathologies. As it plays a limited role in normal human physiology, VEGF is an attractive therapeutic target in diseases where VEGF plays a key role. It was originally thought that in pathological conditions such as cancer, VEGF functioned solely as an angiogenic factor, stimulating new vessel formation and increasing vascular permeability. It has since emerged it plays a multifunctional role where it can also have autocrine pro-survival effects and contribute to tumour cell chemoresistance. In this review we discuss the established role of VEGF in angiogenesis and the underlying mechanisms. We discuss its role as a survival factor and mechanisms whereby angiogenesis inhibition improves efficacy of chemotherapy regimes. Finally, we discuss the therapeutic implications of targeting angiogenesis and VEGF receptors, particularly in cancer therapy.

Animals↗

PubMedDate not supplied

[Angiogenesis in human cerebral ischemia].

OBJECTIVE: We aimed to review current knowledge about angiogenesis processes following stroke and possible benefit of future therapeutic angiogenic-related treatments. DEVELOPMENT: Angiogenesis is a physiopathologic process where new vessels arise from pre-existing ones within different phases: sprouting and maturation. To modulate angiogenesis there is a balance between several promoters like VEGF, bFGF, MMPs, etc. but also with inhibitors or angiostatic molecules such as angiostatin, endostatin, etc. In human pathologies angiogenesis has a dual effect: useful in wound healing, tissue remodelling or ischemic heart disease but harmful in cancer, rheumatoid arthritis or atheroma plaque instability and rupture. Angiogenesis is involved in some cerebrovascular diseases. Following ischemic stroke there is an overexpression of several molecules related with this process, although its finality remains largely unknown. CONCLUSION: Angiogenesis is activated after stroke modifying capillary network. To obtain advantages from angiogenesis, it will be essential to achieve the temporal profile of these molecules in humans, and to investigate if its effects are different in acute or chronic stroke phases. In the future, angiogenesis modulation could take part of a combined stroke therapy.

Angiogenesis Inhibitors↗

PubMed2001

Angiogenesis and G-protein-coupled receptors: signals that bridge the gap.

Angiogenesis is a mechanism that has repercussions in a number of physiological and pathological situations. Vascular endothelial growth factor and basic fibroblast growth factor have understandably received enormous research coverage for being the major mediators of new blood vessel growth, often overshadowing other agonist that also have strong angiogenic potential. We wish to put the spotlight on GPCR agonists that undoubtedly have their word to say on the subject of angiogenesis. In this short review, we will discuss our findings along with the work from other groups on the mechanisms by which GPCR agonists, like thrombin and angiotensin II, control a number of angiogenic signals. A complete understanding of these mechanisms could, by the design of new therapeutic strategies, have a strong impact in clinical oncology.

Angiotensins↗

PubMed2002

Regulation of vascular permeability by vascular endothelial growth factors.

Increased vascular permeability is one of the first stages in both physiological and pathological angiogenesis-the generation of new blood vessels from preexisting vasculature. Although this has been hypothesised to be true in physiological angiogenesis, it is clearly a mark of blood vessel growth in disease. Normal, healthy blood vessel growth (physiological angiogenesis) occurs throughout development as well as during tissue repair and growth in adult tissues. Angiogenesis is also seen in a wide variety of diseases, which include all the major causes of mortality in the West-heart disease, cancer, stroke, vascular disease, and diabetes. Much of this angiogenesis is significantly different from normal blood vessel growth and is termed pathological angiogenesis. Angiogenesis is regulated by vascular growth factors, the most notable being the vascular endothelial growth factor family of proteins (VEGF). These act on specific receptors in the vascular system to stimulate new vessel growth by a number of mechanisms. VEGFs also directly stimulate increased vascular permeability to water and large molecular weight proteins and vasodilatation. These two effects result in a large flux of water and macromolecules from the vasculature to the interstitium, often resulting in oedema. This review will outline the mechanisms by which VEGFs do this and discuss some of the difficulties in interpreting data from VEGF studies due to the conflicting and synergistic effects of these actions.

Animals↗

PubMed2004

Vascular zip codes in angiogenesis and metastasis.

In vivo screening of phage-displayed peptide libraries has revealed extensive molecular differences in the blood vessels of individual normal tissues. Pathological lesions also put their signature on the vasculature; in tumours, both blood and lymphatic vessels differ from normal vessels. The changes that characterize tumour blood vessels include selective expression of certain integrins. Peptides isolated by in vivo phage display for homing to tumours have been shown to be useful in directing therapeutic agents to experimental tumours. The targeting can enhance the efficacy of the therapy while reducing side effects. Phage screening has also revealed lung-specific vascular markers that promote tumour metastasis to the lungs by mediating specific adherence of tumour cells to the lung vasculature. These phage-screening studies have revealed a previously unsuspected degree of vascular specialization and provide potentially useful guidance devices for targeted therapies.

Animals↗

PubMedDate not supplied

Vascular endothelial growth factor and endometriotic angiogenesis.

Peritoneal endometriosis is a significant debilitating gynaecological problem of widespread prevalence. It is now generally accepted that the pathogenesis of peritoneal endometriosis involves the implantation of exfoliated endometrium. Essential for its survival is the generation and maintenance of an extensive blood supply both within and surrounding the ectopic tissue. The vascular endothelial growth factor (VEGF) family of angiogenic molecules is involved in both physiological angiogenesis, and a number of pathological conditions that are characterized by excessive angiogenesis. Increasing evidence suggests that the VEGF family may also be involved with both the aetiology and maintenance of peritoneal endometriosis. Sources of this factor include the eutopic endometrium, ectopic endometriotic tissue and peritoneal fluid macrophages. Important to its aetiology is the correct peritoneal environment in which the exfoliated endometrium is seeded and implants. Established ectopic tissue is then dependent on the peritoneal environment for its survival, an environment that supports angiogenesis. Our increasing knowledge of the involvement of the VEGF family in endometriotic angiogenesis raises the possibility of novel approaches to its medical management, with particular focus on the anti-angiogenic control of the action of VEGF.

Angiogenesis Inhibitors↗

PubMed1998

3D Color Power Angio imaging: a new method to assess intracervical vascularization in benign and pathological conditions.

It is well known that angiogenesis is a fundamental event in the growth of tumors as well as in physiological conditions. In an ongoing prospective study involving eight women, we investigated the microvasculature within the cervix by the use of 3D Color Power Angio imaging. The ultrasound equipment was used in conjunction with specialized software providing high-resolution '3D-Angiomode'. The system provides the ability to visualize blood flow in small vessels that are undetectable by conventional color Doppler techniques and also to study the architecture and determine the number of blood vessels. Comparison of the vessels in the normal cervix with those in the cervix affected by carcinoma or bacterial or viral infection demonstrated that, in malignant tissue, there is a chaotic network of tortuous vessels traversing the tumor mass, whereas, in benign tissue or tissue that is inflamed as a result of infection, the course of the vessels has a regular structure.

Cervix Uteri↗

PubMed2004

Current methods for assaying angiogenesis in vitro and in vivo.

Angiogenesis, the development of new blood vessels from an existing vasculature, is essential in normal developmental processes and in numerous pathologies, including diabetic retinopathy, psoriasis and tumour growth and metastases. One of the problems faced by angiogenesis researchers has been the difficulty of finding suitable methods for assessing the effects of regulators of the angiogenic response. The ideal assay would be reliable, technically straightforward, easily quantifiable and, most importantly, physiologically relevant. Here, we review the advantages and limitations of the principal assays in use, including those for the proliferation, migration and differentiation of endothelial cells in vitro, vessel outgrowth from organ cultures and in vivo assays such as sponge implantation, corneal, chamber, zebrafish, chick chorioallantoic membrane (CAM) and tumour angiogenesis models.

Angiogenesis Modulating Agents↗

PubMed1999

Angiogenesis.

Angiogenesis, the growth and proliferation of blood vessels from existing vascular structures, is tightly regulated in adult tissues, and abnormalities in angiogenesis are associated with a number of pathologic states. Strategies designed to promote angiogenesis to treat disorders of inadequate tissue perfusion, such as occurs in coronary artery and peripheral vascular disease, have led to the area of therapeutic angiogenesis. Approaches to block angiogenesis are actively being explored to treat diseases that range from arthritis to cancer. This article will review some of the basic concepts of vascular development and the mechanisms involved in angiogenesis. Particular attention will be paid to the growth factors and receptors that are known to mediate angiogenesis, and a description of some of the cell signaling mechanisms that are involved in the regulation of angiogenesis will be described. Finally, potential targets that may provide opportunities to enhance or block angiogenesis will be discussed.

Angiogenesis Inhibitors↗

PubMed2007

Molecular imaging of angiogenesis.

Angiogenesis (the growth of new blood vessels) is a complex multistep process that involves multiple cell types, numerous growth factors, and complex regulatory checks and balances. Tight control of vascular remodeling evolved to ensure stability of the vasculature while maintaining the body's ability to rapidly mount an angiogenic response requiring a high degree of plasticity. Angiogenesis is critical not only for physiological development, but also for the progression of pathologies, and is thus a target for therapeutic intervention. The importance of the process coupled with the ease of access for delivery of contrast agents makes the vasculature at large, and angiogenesis in particular, a favorable target of functional and molecular imaging. Recent developments in molecular imaging tools have expanded our views to encompass many components of the process. Functional imaging of blood volume, vessel permeability, and vasoreactivity is complemented by novel contrast agents that reveal specific targets on endothelial cells. Methods have been developed to label vascular cells so as to track their recruitment to sites of angiogenesis, and new "smart" contrast agents have been designed to reveal the activity of enzymatic reactions in altering the extracellular matrix (ECM) during angiogenesis.

Angiogenesis Inducing Agents↗

PubMed2002

A critical review of vascular endothelial growth factor (VEGF) analysis in peripheral blood: is the current literature meaningful?

Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor with a key role in many physiological and pathological processes. Investigation into the implications of circulating levels of this cytokine is progressing at an exponential rate. However, there are important inconsistencies between reports ranging from method of sample collection, processing, software manipulation and data interpretation and controversy as to whether plasma, serum or whole blood will provide the best prognostic information. Different techniques of centrifugation and temperature on sample handling and the impact of in vitro collection of blood on subsequent VEGF results have not been fully appreciated. We provide a critical review of the literature, report the results of our further investigations, suggest a uniform protocol for handling blood samples and highlight previously unsuspected problems in data interpretation.

Blood Specimen Collection↗

PubMed2006

Making the cut: protease-mediated regulation of angiogenesis.

Angiogenesis is an integral element of normal physiologic development as well as of wound healing and a variety of pathologic conditions. Since the earliest studies of the cellular processes required for the formation of new capillaries from preexisting vessels, proteolysis has been recognized as one of the earliest and most sustained activities involved in these events. Several proteases including matrix metalloproteases (MMPs), and the closely related ADAM (a disintegrin and metalloprotease domain) and ADAMTS (a disintegrin and metalloprotease domain with thrombospondin motifs) families, as well as cysteine and serine proteases, have been implicated in this regulation. The current review addresses the contribution of these proteases in the positive and negative regulation of angiogenesis as mediated by degradation of the endothelial basement membrane and extracellular matrix proteins, release of angiogenic factors, processing of cytokines, growth factors and growth factor receptors, and the production of endogenous inhibitors.

Animals↗

PubMed2003

Angiogenesis: vascular remodeling of the extracellular matrix involves metalloproteinases.

Endothelial cell invasion is an essential event during angiogenesis (the formation of new blood vessels). This process involves the degradation of the extracellular matrix, the basement membrane, and interstitial stroma, and is governed by the activation of matrix metalloproteinases. However, the contribution of matrix metalloproteinases in angiogenesis is much more complicated. Tumor growth above a certain size is dependent on new vessels. A number of studies have demonstrated that treating tumors with matrix metalloproteinase inhibitors results in tumor reduction and a decrease in tumor angiogenesis. Matrix metalloproteinases as sole matrix eaters or degraders is a matter of the past. Not only tumor cells but more importantly bystander cells such as stromal cells produce matrix metalloproteinases. Matrix metalloproteinases therefore are also part of the pathologic microenvironment in different diseases. This enzymatic microenvironment dictates the endothelial cell fate, the angiogenic switch, and finally angiogenesis. During recent years, the role of matrix metalloproteinases has expanded, and their function as modulators of biologically active signaling molecules has drawn much attention. Depending on their substrate (growth factors or their receptors, extracellular matrix components, and angiogenic factors), matrix metalloproteinase activation results in the generation of proangiogenic or antiangiogenic factors. These data challenge the old concept that matrix metalloproteinases are simply proangiogenic. The knowledge of the local enzymatic profile and what, where, and how matrix metalloproteinases are involved in angiogenesis of tumors or other diseases will help design future therapeutic strategies better reflecting the complexity of the underlying biologic process of angiogenesis.

Animals↗