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PubMed2000

VEGF: an update on biological and therapeutic aspects.

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and an angiogenic inducer as well as a mediator of vascular permeability. VEGF is essential for developmental angiogenesis and is also required for female reproductive functions and endochondral bone formation. Substantial evidence also implicates VEGF in tumors and intraocular neovascular syndromes. Currently, several clinical trials are ongoing to test the hypothesis that the inhibition of VEGF activity may be beneficial for these conditions.

Animals↗
PubMed2003

Endothelial progenitor cells: precursors for angiogenesis.

The presence of endothelial progenitor cells has been demonstrated in the bone marrow and systemic circulation of adults, thus raising the possibility of a novel strategy to induce therapeutic angiogenesis for ischemic arterial disease. Successful incorporation into sites of actively occurring angiogenesis in numerous animal models has accelerated the enthusiasm for exploiting their therapeutic capacity in humans and has led to the recent use of putative endothelial precursor cells in phase I feasibility and safety studies. However, key biological issues remain ill defined. The relative contribution of these cells to postnatal physiological and pathological neovascularization has not been fully characterized. Furthermore, the molecular phenotype of the putative endothelial progenitor cell and the processes leading to their mobilization from the bone marrow and homing to sites of angiogenesis have yet to be elucidated. This review addresses these fundamental issues that warrant further basic investigation before the full therapeutic potential of these cells can be achieved within appropriate target patients.

Adult↗
PubMed2001

Role of Id proteins in embryonic and tumor angiogenesis.

It has been shown recently in mouse model systems that the Id proteins play a critical role in angiogenesis both during embryogenesis and tumor formation. The Id proteins are intracellular proteins that inhibit the activity of differentiation-promoting transcription factors and thereby block differentiation and promote cell cycle progression. Loss of Id function in mice leads to premature neural differentiation and withdrawal from the cell cycle in neurons and also the execution of an aberrant differentiation cascade in endothelial cells. This latter event is associated with a mid-gestational brain hemorrhage when Id dosage is sufficiently low. Partial reduction in Id levels spares the endothelium in the brain but adults born fail to support the vascularization of tumors. Through the analysis of these phenotypes and characterization of altered gene expression in the Id knockout endothelium, subdivisions in the angiogenic process are being defined which may lead to selective anti-angiogenic treatments in the management of human disease.

Animals↗
PubMed2004

Angiogenesis model for ultrasound contrast research: exploratory study.

RATIONALE AND OBJECTIVES: To optimize an angiogenesis model for imaging research that is stable and can be imaged several times over the angiogenic time course. MATERIALS AND METHODS: Mice and rats received two injections of 0.4 mL of extract of basement membrane matrix (Matrigel; Becton Dickinson Labware, Bedford, MA) in the subcutaneous spaces on either side of the spine. One of the two Matrigel plugs in each animal had either 0.1 microg/mL of basic fibroblast growth factor (bFGF) (11 mice), 1.0 microg/mL of bFGF (12 mice, 5 rats), or 1.0 microg/mL of bFGF and 60 U/mL of heparin (11 mice). Three to 12 days after implantation, animals were imaged before and after the administration of up to four injections of 0.1 mL AF0150. Phase inversion imaging was used on a Siemens Elegra (Siemens ultrasound, Issaquah, WA) equipped with a 13 MHz VFX transducer. Three observers subjectively assessed the pattern of enhancement using a four-point scale. The Matrigel plugs were then removed and two observers graded the angiogenic response on a four-point scale. Ten Matrigel plugs, five with 1.0 microg/mL bFGF and five without, were evaluated histologically following immunohistochemical staining with anti-CD31. RESULTS: The angiogenic response was greater in Matrigel plugs with 1.0 than with 0.1 microg/mL of bFGF. Heparin did not increase the angiogenic response. Vessels were predominantly at the periphery of the plugs with variable central penetration. Plugs appeared anechoic and homogeneous on ultrasound. Contrast enhancement within the plug occurred in 44% of mice with an angiogenic response at or after day 6 and the enhancement increased with the angiogenic response. In the others, peripheral enhancement could not be distinguished from the enhancement of surrounding tissues that were also hyperemic. The thicker rat skin interfered with plug assessment. CONCLUSION: A stable angiogenesis model without the complexity of tumors is described. This model offers the opportunity to image the development and/or inhibition of angiogenesis. Neovasculature in Matrigel was detectable using ultrasound contrast. Quantitative studies correlating the degree of enhancement to microvascular density will be determined in subsequent studies.

Animals↗
PubMed1999

Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability.

Src kinase activity was found to protect endothelial cells from apoptosis during vascular endothelial growth factor (VEGF)-, but not basic fibroblast growth factor (bFGF)-, mediated angiogenesis in chick embryos and mice. In fact, retroviral targeting of kinase-deleted Src to tumor-associated blood vessels suppressed angiogenesis and the growth of a VEGF-producing tumor. Although mice lacking individual Src family kinases (SFKs) showed normal angiogenesis, mice deficient in pp60c-src or pp62c-yes showed no VEGF-induced vascular permeability (VP), yet fyn-/- mice displayed normal VP. In contrast, inflammation-mediated VP appeared normal in Src-deficient mice. Therefore, VEGF-, but not bFGF-, mediated angiogenesis requires SFK activity in general, whereas the VP activity of VEGF specifically depends on the SFKs, Src, or Yes.

Animals↗
PubMed2000

CEA-related cell adhesion molecule 1: a potent angiogenic factor and a major effector of vascular endothelial growth factor.

CEA-related cell adhesion molecule 1 (CEACAM1) exhibits angiogenic properties in in vitro and in vivo angiogenesis assays. CEACAM1 purified from granulocytes and endothelial cell media as well as recombinant CEACAM1 expressed in HEK293 cells stimulate proliferation, chemotaxis, and capillary-like tube formation of human microvascular endothelial cells. They increase vascularization of chick chorioallantoic membrane and potentiate the effects of vascular endothelial growth factor (VEGF)165. VEGF165 increases CEACAM1 expression both on the mRNA and the protein level. VEGF165-induced endothelial tube formation is blocked by a monoclonal CEACAM1 antibody. These data suggest that CEACAM1 is a major effector of VEGF in the early microvessel formation. Since CEACAM1 is expressed in tumor microvessels but not in large blood vessels, CEACAM1 may be a target for the inhibition of tumor angiogenesis.

Adenosine Triphosphatases↗
PubMed1998

Endothelial cell stimulating angiogenesis factor.

Endothelial cell stimulating angiogenesis factor (ESAF) is a small (> 1000 Da) dialysable non-peptide molecule with potent angiogenic activity. ESAF activates the major pro-matrix metalloproteinases and also uniquely reactivates the complex of these active enzymes with their tissue inhibitors resulting in both active enzyme and inhibitor. These actions may be pivotal in its role as an angiogenic factor. ESAF is primarily involved in angiogenic conditions where inflammatory cells are not evident such as foetal bone growth and electrically stimulated skeletal muscles and proliferative retinopathy. However, high levels also occur in actively growing human intracranial tumours but it is not noticeably elevated in rheumatoid arthritic synovial fluid. Its extreme potency and low molecular mass make its structural determination difficult. Possible therapeutic applications would be in the treatment of ischaemic ulcers, acceleration of fracture repair, infertility and more modestly in the correction of baldness. Analogues of ESAF could be of value in treating angiogenic diseases such as psoriasis and proliferative retinopathy.

Angiogenesis Inducing Agents↗
PubMed1997

Growth factors in angiogenesis: current interest and therapeutic potential.

Angiogenesis, the process of new blood vessel development, is an essential component of the body's physiology and contributes to the pathogenesis of a variety of diseases such as benign and malignant neoplasia and rheumatoid arthritis. Failure of this physiological response is also important in abnormalities of wound healing in diseases such as duodenal ulceration and diabetes. Angiogenesis is controlled by a variety of factors that initiate, control and terminate this complex, multi-stage process. This review covers those factors that are exciting much interest currently and have potential for incorporation into clinical medicine.

Animals↗
PubMed2002

The ephrins and Eph receptors in angiogenesis.

Eph receptors are a unique family of receptor tyrosine kinases that play critical roles in embryonic patterning, neuronal targeting, vascular development and adult neovascularization. Engagement of Eph receptors by ephrin ligands mediates critical steps of angiogenesis, including juxtacrine cell-cell contacts, cell adhesion to extracellular matrix, and cell migration. Recent evidence from in vitro angiogenesis assays and analysis of mice deficient for one or more members of the Eph family establishes the role of Eph signaling in sprouting angiogenesis and blood vessel remodeling during vascular development. Furthermore, elevated expression of Eph receptors and ephrin ligands is associated with tumors and associated tumor vasculature, suggesting that Eph receptors and their ephrin ligands also play critical roles in tumor angiogenesis and tumor growth. This review will focus on the relevance of Eph receptor signaling in embryonic and adult neovascularization, and possible contributions to tumor growth and metastasis.

Animals↗
PubMed2002

Lipid mediators of angiogenesis and the signalling pathways they initiate.

Investigations carried out over the past 3 years have implicated a key role for sphingosine 1-phosphate (SPP) in angiogenesis and blood vessel maturation. SPP is capable of inducing almost every aspect of angiogenesis and vessel maturation in vitro, including endothelial cell chemotaxis, survival, proliferation, capillary morphogenesis and adherence antigen deployment, as well as stabilizing developing endothelial cell monolayers and recruitment of smooth muscle cells to maturing vessels. Acting in conjunction with protein angiogenic factors, SPP induces prolific vascular development in many established models of angiogenesis in vivo. Thus, SPP is a unique, potent and multifaceted angiogenic agent. While SPP induces angiogenic effects by ligating members of the endothelial differentiation gene (EDG) G-protein-coupled family of receptors, recent studies suggest that endogenously produced SPP may also account for the ability of tyrosine kinase receptors to induce cell migration. Thus, SPP provides a clear link between tyrosine kinase and G-protein-coupled receptor agonists involved in the angiogenic response. However, the mechanisms by which SPP exerts its effects on vascular cells remain unclear, conflicting and controversial. Precise definition of the signalling pathways by which SPP induces specific aspects of the angiogenic response promises to lead to new and effective therapeutic approaches to regulate angiogenesis at sites of tissue damage, neoplastic transformation and inflammation. This review will trace the discovery of SPP as a novel angiogenic factor as it outlines present information on the signalling pathways by which SPP induces its effects on cells of the developing vascular bed.

Animals↗
PubMed1997

The preclinical evaluation of angiogenesis inhibitors.

Angiogenesis is a fundamental process which is required for a number of physiological and pathophysiological processes. The field of angiogenesis therefore has many therapeutic implications and has progressed rapidly. Many strategies have been devised to regulate angiogenesis and several endogenous and synthetic inhibitors of angiogenesis have now been identified. These inhibitors can be used to treat a number of angiogenesis-dependent diseases and they offer a novel means of potently inhibiting tumor growth without significant toxicity or drug resistance. Recently, some of these inhibitors have entered clinical trials. In this article, I will review methods currently employed in the preclinical evaluation of angiogenesis inhibitors and I will discuss some of the implications of angiogenesis research.

Allantois↗
PubMed1997

An overview of clinical trials involving inhibitors of angiogenesis and their mechanism of action.

Angiogenesis is a biologic process whereby endothelial cells divide and migrate to form new blood vessels. This process is required in physiological conditions, but is also a necessary requirement for solid tumors to grow and metastasize. Over the last several years, the growth factors that have both a positive and negative influence on tumor angiogenesis have been delineated. Interfering with tumor angiogenesis was considered a potential therapeutic strategy 25 years ago, but only recently have compounds with an ability to interfere with angiogenesis entered clinical trials. This review will discuss the first generation of angiogenesis inhibitors, their mechanism of action and data from clinical trials.

Antibiotics, Antineoplastic↗