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Results for “Neovascularization, Pathologic”

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At least 505 records · Page 28Linked to original sources
PubMed2005

The role of notch in modeling and maintaining the vasculature.

The Notch proteins encompass a family of transmembrane receptors that have been highly conserved through evolution as mediators of cell fate, and are comprised of 4 members in mammals (Notch1 to Notch4). Following intra cellular processing of the full-length protein, Notch is expressed at the cell surface as a heterodimeric receptor. Engagement by ligand results in a 2-step cleavage of the Notch heterodimer, releasing the intracellular domain of Notch and allowing translocation to the nucleus. The intracellular domain of Notch interacts with the DNA-binding factor, CSL, resulting in transactivation at various promoters, in particular those of various basic helix-loop-helix factors of the HES (Hairy and Enhancer of Split) and HRT families (Hairy-Related Transcription factor). Recent findings implicate Notch as playing a critical and non-redundant role in vascular development and maintenance. This article briefly reviews vessel development and Notch signaling and highlights studies that examine Notch functions such as proliferation, cell survival, migration, adhesion, and mesenchymal transformation in the vasculature. Human diseases caused by Notch pathway members are also discussed.

Animals↗
PubMed2003

Structural, functional, and molecular MR imaging of the microvasculature.

Magnetic resonance imaging (MRI) is widely applied for functional imaging of the microcirculation and for functional and structural studies of the microvasculature. The interest in the capabilities of MRI in noninvasively monitoring changes in vascular structure and function expanded over the past years, with specific efforts directed toward the development of novel imaging methods for quantification of angiogenesis. Molecular imaging approaches hold promise for further expansion of the ability to characterize the microvasculature. Exciting applications for MRI are emerging in the study of the biology of microvessels and in the evaluation of potential pharmaceutical modulators of vascular function and development, and preclinical MRI tools can serve for the design of mechanism-of-action-based noninvasive clinical methods for monitoring response to therapy. The aim of this review is to provide a current snapshot of recent developments in this rapidly evolving field.

Animals↗
PubMed2001

Thrombospondins: multifunctional regulators of cell interactions.

Thrombospondins are secreted, multidomain macromolecules that act as regulators of cell interactions in vertebrates. Gene knockout mice constructed for two members of this family demonstrate roles in the organization and homeostasis of multiple tissues, with particularly significant activities in the regulation of angiogenesis. This review discusses the functions of thrombospondins with regard to their cellular mechanisms of action and highlights recent advances in understanding how multifactorial molecular interactions, at the cell surface and within extracellular matrix, produce cell-type-specific effects on cell behavior and the organization of matrix and tissues.

Animals↗
PubMed2002

Signaling pathways in vascular development.

The vasculature is one of the most important and complex organs in the mammalian body. The first functional organ to form during embryonic development, the intricately branched network of endothelial and supporting periendothelial cells is essential for the transportation of oxygen and nutrients to and the removal of waste products from the tissues. Serious disruptions in the formation of the vascular network are lethal early in post-implantation development, while the maintenance of vessel integrity and the control of vessel physiology and hemodynamics have important consequences throughout embryonic and adult life. A full understanding of the signaling pathways of vascular development is important not just for understanding normal development but because of the importance of reactivation of angiogenic pathways in disease states. Clinically there is a need to develop therapies to promote new blood vessel formation in situations of severe tissue ischemia, such as coronary heart disease. In addition, there is considerable interest in developing angiogenic inhibitors to block the new vessel growth that solid tumors promote in host tissue to enhance their own growth. Already studies on the signaling pathways of normal vascular development have provided new targets for therapeutic intervention in both situations. Further understanding of the complexities of the pathways should help refine such strategies.

Animals↗
PubMed2005

Endothelial progenitor cells.

Endothelial progenitor cells are a circulating, bone marrow-derived cell population that appears to participate in both vasculogenesis and vascular homeostasis. Questions persist regarding their functional characteristics, as well as the precise panel of cell surface markers that uniquely define this newly described progenitor cell population. We review experimental results obtained from both animal studies and recent clinical trials that suggest this cell type may have tremendous therapeutic potential for a wide range of human diseases.

Animals↗
PubMed2004

Novel angiogenic signaling pathways and vascular targets.

Intense investigation into the molecular basis of angiogenesis is rapidly revealing novel signaling pathways involved in the generation of new vasculature. These range from elucidation of the mechanism by which hypoxia initiates expression of a proangiogenic gene repertoire via the hypoxia-inducible transcription factors (HIFs) to molecular pathways involved in extra- and intracellular signaling during new vessel formation. Extracellular pathways include those of the Notch/delta, ephrin/Eph receptor and roundabout/slit families, and intracellular pathway members of the hedgehog and sprouty families. The involvement of these pathways in angiogenesis is discussed, together with some comments on recently identified targets in the vasculature that present new therapeutic opportunities.

Animals↗
PubMed2002

Involvement of human PECAM-1 in angiogenesis and in vitro endothelial cell migration.

Platelet endothelial cell adhesion molecule (PECAM)-1 has been implicated in angiogenesis, but a number of issues remain unsettled, including the independent involvement of human PECAM-1 (huPECAM-1) in tumor angiogenesis and the mechanisms of its participation in vessel formation. We report for tumors grown in human skin transplanted on severe combined immunodeficiency mice that antibodies against huPECAM-1 (without simultaneous treatment with anti-VE-cadherin antibody) decreased the density of human, but not murine, vessels associated with the tumors. Anti-huPECAM-1 antibody also inhibited tube formation by human umbilical vein endothelial cells (HUVEC) and the migration of HUVEC through Matrigel-coated filters or during the repair of wounded cell monolayers. The involvement of huPECAM-1 in these processes was confirmed by the finding that expression of huPECAM-1 in cellular transfectants induced tube formation and enhanced cell motility. These data provide evidence of a role for PECAM-1 in human tumor angiogenesis (independent of VE-cadherin) and suggest that during angiogenesis PECAM-1 participates in adhesive and/or signaling phenomena required for the motility of endothelial cells and/or their subsequent organization into vascular tubes.

Animals↗
PubMed2001

Role of vascular endothelial growth factor in regulation of physiological angiogenesis.

Evidence accumulating over the last decade has established the fundamental role of vascular endothelial growth factor (VEGF) as a key regulator of normal and abnormal angiogenesis. The biological effects of VEGF are mediated by two tyrosine kinase receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2). The signaling and biological properties of these two receptors are strikingly different. VEGF is essential for early development of the vasculature to the extent that inactivation of even a single allele of the VEGF gene results in embryonic lethality. VEGF is also required for female reproductive functions and endochondral bone formation. Substantial evidence also implicates VEGF as an angiogenic mediator in tumors and intraocular neovascular syndromes, and numerous clinical trials are presently testing the hypothesis that inhibition of VEGF may have therapeutic value.

Animals↗
PubMed2005

Ascorbic acid-independent synthesis of collagen in mice.

The mouse has become the most important model organism for the study of human physiology and disease. However, until the recent generation of mice lacking the enzyme gulanolactone oxidase (Gulo), the final enzyme in the ascorbic acid biosynthesis pathway, examination of the role of ascorbic acid in various biochemical processes using this model organism has not been possible. In the mouse, similar to most mammals but unlike humans who carry a mutant copy of this gene, Gulo produces ascorbic acid from glucose. We report here that, although ascorbic acid is essential for survival, its absence does not lead to measurable changes in proline hydroxylation. Vitamin C deficiency had no significant effect on the hydroxylation of proline and collagen production during tumor growth or in angiogenesis associated with tumor or mammary gland growth. This suggests that factors other than ascorbic acid can support proline hydroxylation and collagen synthesis in vivo. Furthermore, the failure of Gulo-/- mice to thrive on a vitamin C-deficient diet therefore suggests that ascorbic acid plays a critical role in survival other than the maintenance of the vasculature.

Animals↗
PubMed1992

Inhibition of bovine retinal microvascular pericyte proliferation in vitro by adenosine.

Adenosine acts on bovine retinal microvascular pericytes through one or more adenosine receptor subtypes present on the cell surface. Retinal pericytes cultured in medium containing adenosine at concentrations from 10(-6) to 10(-4) M showed significant reduction in proliferation following several days in vitro compared with control cultures. The effects of adenosine were mimicked by polyadenylic acid and inhibited by 8-phenyltheophylline, indicating involvement of a cell surface receptor. Metabolites of adenosine had no effect on pericyte proliferation. An A2 adenosine receptor-specific analogue also inhibited pericyte growth, suggesting that inhibition by adenosine is mediated by A2-receptors and might involve a transient increase in adenosine 3',5'-cyclic monophosphate levels. The results of the present study demonstrate that in addition to demonstrated stimulatory effects on capillary endothelial cells, adenosine also has a direct inhibitory effect on retinal pericytes. We hypothesize a dual function of adenosine within the capillary wall resulting in loss of inhibition of endothelial cells and suggest a role for this nucleoside in pathological neovascularization processes such as proliferative diabetic retinopathy.

Adenosine↗
PubMed2001

Alterations of Ca2+ mobilizing properties in migrating endothelial cells.

Endothelial migration is one of the major events of pathological neovascularization. We compared the characteristics of Ca2+ mobilization in nonconfluent, confluent, and migrating endothelial cells. Migration of endothelial cells was induced by wounding the confluent cell monolayer. The basal intracellular Ca2+ concentration was lower in migrating cells and higher in confluent cells than in nonconfluent cells. Thapsigargin (TG)-induced Ca2+ leak and TG-evoked Ca2+ entry were accelerated in migrating cells, whereas the latter was suppressed in confluent cells. The ATP-induced Ca2+ transient was also much larger in migrating cells than in confluent cells. These alterations were also observed in a cell as an intracellular polarization, i.e., the leading edge showed an acceleration of TG-evoked Ca2+ entry and an augmentation of the ATP-induced Ca2+ transient. Endothelial migration was significantly suppressed by TG or cyclopiazonic acid. These observations suggest that the alterations of Ca2+ store site-related Ca2+ mobilizations, i.e., Ca2+ sequestration, release, and TG-evoked Ca2+ entry, may be involved in the cellular mechanisms of endothelial migration.

Animals↗
PubMed2001

Mechanisms of angiotensin-(1-7)-induced inhibition of angiogenesis.

Angiotensin-(1-7) [ANG-(1-7)], an endogenous bioactive peptide constituent of the renin-angiotensin system, acts as an inhibitory growth factor in vitro and in vivo. In this study, we evaluated whether the antiangiogenic effect of ANG-(1-7) in the mouse sponge model of angiogenesis might be receptor mediated and involved in the release of nitric oxide (NO). The hemoglobin content (microg/mg wet tissue) of 7-day-old sponge implants was used as an index of the vascularization and showed that daily injections of ANG-(1-7) (20 ng) inhibited significantly the angiogenesis in the implants relative to the saline-treated group. The specific receptor antagonist D-Ala(7)-ANG-(1-7); A-779 prevented ANG-(1-7)-induced inhibition of angiogenesis. The antiangiogenic effect was also abolished by pretreatment with NO synthase inhibitors aminoguanidine (1 mg/ml) or N(G)-nitro-L-arginine methyl ester (0.3 mg/ml). Selective AT1 and AT2 angiotensin-receptor antagonists and an angiotensin-converting enzyme inhibitor, in combination with ANG-(1-7) or alone, did not alter angiogenesis in the implants. These results establish that the regulation of the vascular tissue growth by ANG-(1-7) is associated with NO release by activation of an angiotensin receptor distinct from AT1 and AT2.

Analysis of Variance↗
PubMed2002

In silico data filtering to identify new angiogenesis targets from a large in vitro gene profiling data set.

The objective of this study was to use gene expression data from well-defined cell culture models, in combination with expression data from diagnostic samples of human diseased tissues, to identify potential therapeutic targets and markers of disease. Using Affymetrix oligonucleotide array technology, we identified a common profile of genes upregulated during endothelial morphogenesis into tubelike structures in three in vitro models of angiogenesis. Rigorous data selection criteria were used to identify a list of over 1,000 genes whose expression was increased more than twofold over baseline at either 4, 8, 24, 40 or 50 h. To further refine and prioritize this list, we used standard bioinformatic algorithms to identify potential transmembrane and secreted proteins. We then overlapped this gene set with genes upregulated in colon tumors vs. normal colon, resulting in a subset of 128 genes in common with our endothelial list. We removed from this list those genes expressed in 6 different colon tumor lines, resulting in a list of 24 putative, vascular-specific angiogenesis-associated genes. Three genes, gp34, stanniocalcin-1 (STC-1), and GA733-1, were expressed at levels 10-fold or more in colon tumors compared with normal mucosa. We validated the vascular-specific expression of one of these genes, STC-1, by in situ hybridization. The ability to combine in vitro and in vivo data sets should permit one to identify putative angiogenesis target genes in various tumors, chronic inflammation, and other disorders where therapeutic manipulation of angiogenesis is a desirable treatment modality.

Animals↗
PubMed2004

Endothelial cell surface ATP synthase-triggered caspase-apoptotic pathway is essential for k1-5-induced antiangiogenesis.

We have recently reported the identification of kringle 1-5 (K1-5) of plasminogen as a potent and specific inhibitor of angiogenesis and tumor growth. Here, we show that K1-5 bound to endothelial cell surface ATP synthase and triggered caspase-mediated endothelial cell apoptosis. Induction of endothelial apoptosis involved sequential activation of caspases-8, -9, and -3. Administration of neutralizing antibodies directed against the alpha- and beta-subunits of ATP synthase to endothelial cells attenuated activation of these caspases. Furthermore, inhibitors of caspases-3, -8, and -9 also remarkably blocked K1-5-induced endothelial cell apoptosis and antiangiogenic responses. In a mouse tumor model, we show that caspase-3 inhibitors abolished the antitumor activity of K1-5 by protecting the tumor vasculature undergoing apoptosis. These results suggest that the specificity of the antiendothelial effect of K1-5 is attributable, at least in part, to its interaction with the endothelial cell surface ATP synthase and that the caspase-mediated endothelial apoptosis is essential for the angiostatic activity of K1-5. Thus, our findings provide a mechanistic insight with respect to the angiostatic action and signaling pathway of K1-5 and angiostatin.

ATP Synthetase Complexes↗