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Results for “Angiogenesis Modulating Agents”

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At least 19 recordsLinked to original sources
PubMed2003

Endothelial-directed hepatic regeneration after partial hepatectomy.

OBJECTIVE: To determine the role of the microvascular endothelium in the regulation of regenerating liver mass after partial hepatectomy. SUMMARY BACKGROUND DATA: Angiogenesis is critical for both pathologic and physiologic processes. The ability of certain tissues, such as the liver, kidney, and spleen, to regenerate after injury is poorly understood. The liver will regenerate to its normal mass within 8 days of surgical excision. Because the authors have previously shown that the endothelial cell regulates tumor mass, we hypothesized that normal adult organ mass is also controlled by the endothelial cell. METHODS: Two-thirds partial hepatectomy was performed in 7- to 8-week-old C57 BL/6 mice, followed by systemic treatment with either the angiogenesis stimulator basic fibroblast growth factor (bFGF) (1 microg/g/d intraperitoneal) or the angiogenesis inhibitor TNP-470 (30 mg/kg/qod subcutaneous). Groups of three mice were then euthanized on postoperative days 2, 4, 6, and 8, and the livers were weighed and analyzed by immunohistochemistry. RESULTS: bFGF accelerated hepatic regeneration by 42%, 19%, 16%, and 16% on postoperative days 2, 4, 6, and 8, respectively. TNP-470 inhibited hepatic regeneration by 46%, 74%, 67%, and 64% on postoperative days 2, 4, 6, and 8, respectively. Immunohistochemistry revealed that bFGF and TNP-470 primarily affected the endothelial compartment. Specifically, bFGF increased endothelial proliferation and decreased endothelial apoptosis. TNP-470, in contrast, inhibited endothelial cell proliferation. The cessation of the regenerative process correlated with a decrease in endothelial proliferation and an increase in endothelial apoptosis. CONCLUSIONS: The systemic administration of angiogenesis agents modulates the regeneration of hepatic mass primarily by affecting endothelial cell proliferation or apoptosis. Endothelial cell apoptosis is associated with the cessation of the regenerative process in control mice. These results suggest that the endothelial cell is one of the key mediators of regenerating adult tissue mass in this partial hepatectomy model.

Animals↗
PubMed2002

Angiogenesis modulation in cancer research: novel clinical approaches.

Angiogenesis--the formation of new blood vessels--is essential for tumour progression and metastasis. Consequently, the modulation of tumour angiogenesis using novel agents has become a highly active area of investigation in cancer research, from the bench to the clinic. However, the great therapeutic potential of these agents has yet to be realized, which could, in part, be because the traditional strategies that are used in clinical trials for anticancer therapies are not appropriate for assessing the efficacy of agents that modulate angiogenesis. Here, we discuss methods for monitoring the biological activity of angiogenic modulators, and innovative approaches to trial design that might facilitate the integration of these agents into anticancer therapy.

Angiogenesis Inhibitors↗
PubMed2002

Microarray technology and gene expression analysis for the study of angiogenesis.

Angiogenesis plays a major role in multiple disease processes including cancer, and new agents that modulate angiogenesis are rapidly entering clinical trials. The understanding of the biological mechanisms and downstream effects for many of these agents is poorly understood. It is therefore important that methods evolve to understand how an agent regulates angiogenesis, in order to promote a higher percentage of successful drug candidates. With the emergence of microarray technology for the evaluation of gene expression, researchers have a powerful tool for dissecting the biological mechanisms of angiogenesis. However, huge data sets and complex statistics pose a hurdle for the investigator to obtain useful and meaningful data. To eliminate problems in data analysis, proper design and planning prior to performing a microarray experiment is crucial to making valid conclusions. This review will discuss the critical factors in designing, performing and analysing microarray experiments, and the utility of various models of angiogenesis for microarray analysis.

Animals↗
PubMed2006

Evaluation of original dual thromboxane A2 modulators as antiangiogenic agents.

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A(2) (TXA(2)) inhibitors derived from torasemide, a marketed loop diuretic with TXA(2) antagonistic properties, by evaluating their effects on human endothelial cell migration, adhesion, and viability in vitro, as well as in the ex vivo rat aortic ring assay. All drugs tested exhibited a marked affinity toward human platelet TXA(2) receptor, significantly prevented platelet aggregation induced by U-46,619, a stable TXA(2) receptor agonist, and inhibited platelet TXA(2) synthase without affecting cyclooxygenase (COX)-1 or COX-2 enzymatic activities. These dual TXA(2) inhibitors dose dependently inhibited endothelial cell migration in chemotaxis assays using vascular endothelial growth factor (VEGF) as a chemoattractant but failed to affect cell adhesion and viability. The highest rates of cell migration inhibition were obtained with original compounds BM-567 and BM-573 (50.3 and 59.4% inhibition, respectively) when used at the final concentration of 10 microM. In addition, pretreatment of endothelial cells with these two drugs significantly prevented U-46,619-induced intracellular Ca(2+) pool mobilization, thus suggesting a mechanistic link between inhibition of the TXA(2) pathway and reduced endothelial cell migration. Treatment of rat aortic explants with U-46,619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F(2)) significantly enhanced vessel sprouting whereas aortic rings treated with some of the compounds, including BM-567 (N-n-pentyl-N'-[2-(cyclohexylamino)-5-nitrobenzenesulfonyl]urea) and BM-573 (N-tert-butyl-N'-[5-nitro-2-p-toluylaminobenzenesulfonyl]urea), showed a significant decrease in vessel sprouting, which was not reversed by the addition of VEGF. These data suggest that our original dual TXA(2) inhibitors bear antiangiogenic properties, mainly by inhibiting endothelial cell migration.

Angiogenesis Inhibitors↗
PubMed2006

Preparation and use of microarrays containing synthetic heparin oligosaccharides for the rapid analysis of heparin-protein interactions.

Heparin is a highly sulfated, linear polymer that participates in a plethora of biological processes by interaction with many proteins. The chemical complexity and heterogeneity of this polysaccharide can explain the fact that, despite its widespread medical use as an anticoagulant drug, the structure-function relationship of defined heparin sequences is still poorly understood. Here, we present the chemical synthesis of a library containing heparin oligosaccharides ranging from di- to hexamers of different sequences and sulfation patterns. An amine-terminated linker was placed at the reducing end of the synthetic structures to allow for immobilization onto N-hydroxysuccinimide activated glass slides and creation of heparin microarrays. Key features of this modular synthesis, such as the influence of the amine linker on the glycosidation efficiency, the use of 2-azidoglucose as glycosylating agents for oligosaccharide assembly, and the compatibility of the protecting group strategy with the sulfation-deprotection steps, are discussed. Heparin microarrays containing this oligosaccharide library were constructed using a robotic printer and employed to characterize the carbohydrate binding affinities of three heparin-binding growth factors. FGF-1, FGF-2 and FGF-4 that are implicated in angiogenesis, cell growth and differentiation were studied. These heparin chips aided in the discovery of novel, sulfated sequences that bind FGF, and in the determination of the structural requirements needed for recognition by using picomoles of protein on a single slide. The results presented here highlight the potential of combining oligosaccharide synthesis and carbohydrate microarray technology to establish a structure-activity relationship in biological processes.

Angiogenesis Modulating Agents↗
PubMed2004

Anti-angiogenic effects of thalidomide: expression of apoptosis-inducible active-caspase-3 in a three-dimensional collagen gel culture of aorta.

The anti-angiogenic properties of thalidomide have led to the use of the agent as a remedy for multiple myeloma. Nevertheless, the anti-angiogenic moiety of thalidomide remains unidentified. In this study we examined the anti-angiogenic effects of thalidomide in an in vitro model using a three-dimensional collagen gel culture. Angiogenesis was significantly inhibited when the culture was treated with thalidomide plus cytochrome P-450 (CYP2B4), and the migrating cells and tubules were positive for active-caspase-3 in an accompanying immunohistochemical investigation. Transmission electron microscopic observation also confirmed that active-caspase-3-positive cells demonstrated apoptotic characteristics. This study is the first to morphologically demonstrate the effect of thalidomide in directly inducing the apoptosis of new tubules and migrating cells on a three-dimensional collagen gel culture of aorta. Taken together with earlier findings, our new results indicate that the thalidomide-induced inhibition of angiogenesis involves apoptosis in addition to the suppression of TNF-alpha and inhibition of cell migration from aorta explants, i.e., the factors important for capillarogenesis.

Angiogenesis Modulating Agents↗
PubMed2005

Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction.

BACKGROUND: There are several reports that engrafted mesenchymal stem cells (MSCs) stimulate angiogenesis in the ischemic heart, but the mechanism remains controversial. We hypothesize that transplantation of MSCs enhances vascular regeneration through a paracrine action. METHODS: A transmural myocardial infarction was created by ligation of the left anterior descending coronary artery in rats. Those with an ejection fraction less than 0.70 1 week after myocardial infarction were included. Autologous MSCs (1 x 10(7); 0.2 mL) or culture medium (0.2 mL) was injected intramyocardially into the periinfarct zone (50 microL/injection at four sites; n = 20/group). At 2 weeks after transplantation, Western blot analysis was used to assay the paracrine factors and proapoptotic proteins. Echocardiography to assess heart function was performed on additional groups at 8 weeks after implantation. RESULTS: The angiogenic factors basic fibroblast growth factor, vascular endothelial growth factor, and stem cell homing factor (stromal cell-derived factor -1alpha) increased in the MSC-treated hearts compared with medium-treated hearts. This was accompanied by a downregulation of proapoptotic protein Bax in ischemic myocardium. Similarly, capillary density increased about 40% in MSC-treated hearts compared with medium-treated hearts (p = 0.001). Left ventricular contractility, indicated by fractional shortening, improved in MSC-treated hearts at 2 months after implantation (MSCs: 48.6% +/- 19.9%; medium: 18.7% +/- 6.4%; p = 0.004). CONCLUSIONS: Autologous MSC transplantation attenuates left ventricular remodeling and improves cardiac performance. The major mechanism appears to be paracrine action of the engrafted cells, increasing angiogenesis and cytoprotection.

Angiogenesis Modulating Agents↗
PubMed2004

Apelin is a novel angiogenic factor in retinal endothelial cells.

There has been much focus recently on the possible functions of apelin, an endogenous ligand for the orphan G-protein-coupled receptor APJ, in cardiovascular and central nervous systems. We report a new function of apelin as a novel angiogenic factor in retinal endothelial cells. The retinal endothelial cell line RF/6A highly expressed both apelin and APJ transcripts, while human umbilical venous endothelial cells (HUVECs) only expressed apelin mRNA. In accordance with these observations, apelin at concentrations of 1 pM-1 microM significantly enhanced migration, proliferation, and capillary-like tube formation of RF/6A cells, but not those of HUVECs, whereas VEGF stimulates those parameters of both cell types. In vivo Matrigel plug assay for angiogenesis, the inclusion of 1 nM apelin in the Matrigel resulted in clear capillary-like formations with an increase of hemoglobin content in the plug. This is the first report showing that apelin is an angiogenic factor in retinal endothelial cells.

Adipokines↗
PubMed2005

Expression of angiogenesis factors in human umbilical vein endothelial cells and their regulation by PEDF.

The VEGFs and FGF-2 stimulate angiogenesis. Pigment epithelium-derived factor (PEDF) and thrombospondin-1 (TSP-1) strongly inhibit angiogenesis. Human umbilical vein endothelial cells (HUVECs) expressed VEGF-A, -B, -C, the VEGF receptors R1, R2, and R3, PEDF, FGF-2, and TSP-1, but VEGF-D transcripts were barely detectable. Hypoxia reduced the transcript levels of VEGF-C and its cognate receptor, VEGF-R3. PEDF blocked the effect of CoCl(2) on these two factors. The expression of VEGF-A and -B as well as VEGF-R1 and VEGF-R2 remained unchanged after exposure to hypoxia, PEDF, or both. There was a marked reduction in TSP-1 transcripts in CoCl(2) treated cultures and PEDF blocked this reduction. PEDF induced a small increase in FGF-2 transcripts in HUVECs, but there was no change in FGF-2 expression in HUVECs exposed to hypoxia or hypoxia plus PEDF. PEDF may control neovascularization, in part, by restoring the negative effects of hypoxia on the expression of a potent angiogenesis inhibitor, TSP-1. PEDF may also modulate vascular leakage by maintaining the transcriptional levels of the vascular homeostasis factors, VEGF-C and VEGF-R3 in hypoxic conditions.

Angiogenesis Modulating Agents↗
PubMed2005

CXC chemokines in angiogenesis.

CXC chemokines display pleiotropic effects in immunity, regulating angiogenesis, and mediating organ-specific metastases of cancer. In the context of angiogenesis, CXC chemokines are a unique family of cytokines, known for their ability to behave in a disparate manner in the regulation of angiogenesis. Members that contain the 'ELR' motif are potent promoters of angiogenesis, and mediate their angiogenic activity via binding and activating CXCR2 on endothelium. In contrast, members, in general, those are inducible by interferons and lack the ELR motif (ELR-) are potent inhibitors of angiogenesis, and bind to CXCR3 on endothelium. This review will discuss the biology of these angiogenic and angiostatic CXC chemokines and discuss their disparate angiogenic activity in the context of a variety of disorders.

Angiogenesis Modulating Agents↗
PubMed2005

Does Trypanosoma cruzi calreticulin modulate the complement system and angiogenesis?

Calreticulin, a calcium-binding protein that is highly conserved in its multiple functions, is present in a wide spectrum of subcellular compartments in virtually every cell of higher organisms. In this article, we propose a dual role for parasite calreticulin, with emphasis on the Trypanosoma cruzi model. By modulating the vertebrate complement system, calreticulin might provide the parasite with an effective immune-escape mechanism. Alternatively, by inhibiting angiogenesis, the parasite molecule might protect the host from ongoing neoplasic aggressions. Many questions are still unanswered, particularly those regarding the consequences that these interactions could have in vivo for both the parasite and the host.

Angiogenesis Modulating Agents↗
PubMed2006

Vasoinhibins: endogenous regulators of angiogenesis and vascular function.

Vasoinhibins are a family of peptides derived from prolactin, growth hormone and placental lactogen that act on endothelial cells to suppress vasodilation and angiogenesis and to promote apoptosis-mediated vascular regression. Some of the pathways by which vasoinhibins act have now been defined, and recent developments indicate that endogenous vasoinhibins exert tonic and essential actions on blood vessel growth, dilation and regression in vivo. By studying the pathways that can generate vasoinhibins, and the nature of their receptors and key biological mediators, it should be possible to clarify the role of vasoinhibins in controlling vascular function in health and disease.

Angiogenesis Modulating Agents↗
PubMed2003

The aging of the retina.

This mini-review summarizes our current knowledge concerning the age-related changes that affect the retina. Over the last 10 years, our understanding of the genetics of hereditary retinal diseases has improved considerably. However, the modifications that occur in the retina as a result of aging are still under investigation. In this review, we place particular emphasis on the normal retinal alterations that occur with aging (gene modulation; psychophysical, structural and cellular alterations). We describe the events that occur during the pathological aging process, such as in age-related macular degeneration. Understanding these different modifications is essential if we are to find key players on which to base therapeutic interventions that may help to prevent the passage of normal aging process to the pathological aging process.

Aged↗
PubMed2004

COMP-Ang1: a designed angiopoietin-1 variant with nonleaky angiogenic activity.

Angiopoietin-1 (Ang1) has potential therapeutic applications in inducing angiogenesis, enhancing endothelial cell survival, and preventing vascular leakage. However, production of Ang1 is hindered by aggregation and insolubility resulting from disulfide-linked higher-order structures. Here, by replacing the N-terminal portion of Ang1 with the short coiled-coil domain of cartilage oligomeric matrix protein (COMP), we have generated a soluble, stable, and potent Ang1 variant, COMP-Ang1. This variant is more potent than native Ang1 in phosphorylating the tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2) receptor and Akt in primary cultured endothelial cells, enhancing angiogenesis in vitro and increasing adult angiogenesis in vivo. Thus, COMP-Ang1 is an effective alternative to native Ang1 for therapeutic angiogenesis in vivo.

Amino Acid Sequence↗
PubMed2003

Angiogenesis--a new goal in peripheral artery occlusive disease therapy.

The vasculature is mostly quiescent in the normal adult, with the exception of the growth of new blood vessels during the female reproductive cycle. Recent advances in the knowledge concerning the molecular changes and the identification of genetic events in this vascular quiescence, as well as in vascular growth, has led to an increasing number of studies in which these phenomena are manipulated. Angiogenesis is the growth of new vessels from existing ones. Although new vessel formation is involved in many pathologic situations, like tumour growth, therapeutic angiogenesis has been presented as a novel method for the treatment of ischemic diseases, like peripheral arterial occlusive disease (PAOD). In experimental studies therapeutic angiogenesis has been produced by recombinant growth-factor protein application as well as by growth factor gene therapy. Most widely studied factors belong to vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF) families. Studies have also shown that, angiogenic growth factors stimulate endothelial cell migration and accelerate endothelial repair by enhancing post-injury re-endothelization. In clinical studies angiogenic therapy has been evaluated in patients with severe vascular diseases. The results have revealed that therapy is well tolerated as well as safe and that angiogenic therapy has a clear biologic effect. However, controlled studies are still needed to answer the question whether therapeutic angiogenesis offers a real clinical benefit to patients with PAOD.

Adult↗
PubMed2004

Bartonella adhesin a mediates a proangiogenic host cell response.

Bartonella henselae causes vasculoproliferative disorders in humans. We identified a nonfimbrial adhesin of B. henselae designated as Bartonella adhesin A (BadA). BadA is a 340-kD outer membrane protein encoded by the 9.3-kb badA gene. It has a modular structure and contains domains homologous to the Yersinia enterocolitica nonfimbrial adhesin (Yersinia adhesin A). Expression of BadA was restored in a BadA-deficient transposon mutant by complementation in trans. BadA mediates the binding of B. henselae to extracellular matrix proteins and to endothelial cells, possibly via beta1 integrins, but prevents phagocytosis. Expression of BadA is crucial for activation of hypoxia-inducible factor 1 in host cells by B. henselae and secretion of proangiogenic cytokines (e.g., vascular endothelial growth factor). BadA is immunodominant in B. henselae-infected patients and rodents, indicating that it is expressed during Bartonella infections. Our results suggest that BadA, the largest characterized bacterial protein thus far, is a major pathogenicity factor of B. henselae with a potential role in the induction of vasculoproliferative disorders.

Adhesins, Bacterial↗
PubMed2006

New insights into the biology of preeclampsia.

Despite recent research progress, the biology of preeclampsia is still poorly understood and neither effective prediction nor causal therapy have yet emerged. Nevertheless, recent studies have documented new and exciting pathophysiological mechanisms for the origin and development of preeclampsia. These studies provide a more differentiated view on alterations of particular peptide systems with strong impact on angiogenesis and cardiovascular regulation in this pregnancy disorder. With the identification of the antiangiogenic factor soluble fms-like tyrosine kinase 1 and the agonistic autoantibody to the angiotensin II type 1 receptor, two factors have been described with a clear linkage to the development of the disease. This review focuses on the most recent and relevant insights into the biology of preeclampsia and develops hypotheses regarding possible links between the reported aspects of preeclampsia.

Angiogenesis Modulating Agents↗