Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In contrast to VEGF and its receptor VEGFR-2, PlGF and its receptor VEGFR-1 have been largely neglected and therefore their potential for therapy has not been previously explored. In this review, we describe the molecular properties of PlGF and VEGFR-1 and how this translates into an important role for PlGF in the angiogenic switch in pathological angiogenesis, by interacting with VEGFR-1 and synergizing with VEGF. PlGF was effective in the growth of new and stable vessels in cardiac and limb ischemia, through its action on different cell types (i.e. endothelial, smooth muscle and inflammatory cells and their precursors) that play a cardinal role in blood vessel formation. Accordingly, blocking its receptor VEGFR-1 with monoclonal antibodies (anti-VEGFR-1 mAb), expressed on al these cell types, successfully attenuated blood vessel formation during cancer, ischemic retinopathy and rheumatoid arthritis. In addition, while blocking this receptor was effective in reducing inflammatory disorders like atherosclerosis and rheumatoid arthritis, blocking the anti-angiogenic receptor VEGFR-2 was without effect. This indicates that in the latter diseases the beneficial effects of anti-VEGFR1 mAb were mainly due to its effect on inflammatory cells. Importantly, VEGFR-1 was also present on hematopoietic stem/progenitor cells, the precursors of inflammatory cells. Thus, these preclinical studies show proof-of-principle that PlGF and VEGFR-1 are promising therapeutic targets to treat angiogenesis and inflammation related disorders. Clinical trials will reveal whether this is also true for patients.
...
PMID:Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. 1287 Dec 69

The endothelial cells lining all vessels of the circulatory system have been recognized as key players in a variety of physiological and pathological settings. They act as regulators of vascular tone via the inducible nitric oxide system and in angiogenesis, the formation of blood vessels de novo. Aberrant regulation of endothelial cells contributes to tumor formation, atherosclerosis, and diseases such as psoriasis and rheumatoid arthritis. Among the most recently discovered growth factors for endothelial cells are newly isolated members of the platelet-derived growth factor/vascular endothelial growth factor (VEGF) family, VEGF-B, VEGF-C, and VEGF-D. VEGF-C is the ligand for the receptor tyrosine kinase VEGFR-3 (also known as Flt4), which is expressed predominantly in lymphatic endothelium of adult tissues, but a proteolytically processed form of VEGF-C can also activate VEGFR-2 of blood vessels. The lymphatic vessels have been known since the 17th century, but their specific roles in health and disease are still poorly understood. With the discovery of VEGF-C and its cognate receptor VEGFR-3, the regulation and functions of this important component of the circulatory system can be investigated.
...
PMID:Vascular endothelial growth factor-C: a growth factor for lymphatic and blood vascular endothelial cells. 1498 53

Critical lower limb ischemia is a common cause for amputation. To develop new therapeutic strategies, more information is needed about molecular mechanisms of tissue responses to ischemic stress and factors inducing angiogenesis. Using a DNA array of 8400 genes, gene expression patterns in human skeletal muscle samples collected from lower limbs amputated due to acute-on-chronic or chronic critical lower limb ischemia, were compared with the control samples collected from the same limb. The results were confirmed by RT-PCR and immunohistochemistry. In acute-on-chronic ischemia, 291 genes were significantly upregulated and 174 genes were downregulated (change in 5.5% of all genes) as compared to control samples. Significant induction of the hypoxia-inducible angiogenic pathway involving hypoxia-inducible factor-1alpha (HIF-1alpha), HIF-2alpha, vascular endothelial growth factor (VEGF) and its angiogenic receptor VEGFR-2, as well as tumor necrosis factor-alpha (TNF-alpha) with its downstream signaling machinery promoting inflammation and cell death, were found in acute-on-chronic ischemia. In chronic critical ischemia, gene expression changes were much less striking than in acute-on-chronic ischemia, with 74 genes significantly upregulated and 34 genes downregulated (change in 1.3% of all genes). In the chronic situation, the anabolic and survival factors, insulin-like growth factor-1 (IGF-1) and IGF-2, were upregulated in atrophic and regenerating myocytes together with attenuated HIF, VEGF, and VEGFR-2 expression in the same cells. In conclusion, acute-on-chronic and chronic human skeletal muscle ischemia result in distinct gene expression patterns. These findings may be of importance in the design of novel therapies, such as therapeutic vascular growth, for patients suffering from lower limb ischemia.
Atherosclerosis 2004 May
PMID:HIF-VEGF-VEGFR-2, TNF-alpha and IGF pathways are upregulated in critical human skeletal muscle ischemia as studied with DNA array. 1513 59

UTP stimulates the expression of pro-inflammatory vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells through activation of the P2Y(2) nucleotide receptor P2Y(2)R. Here, we demonstrated that activation of the P2Y(2)R induced rapid tyrosine phosphorylation of vascular endothelial growth factor receptor (VEGFR)-2 in human coronary artery endothelial cells (HCAEC). RNA interference targeting VEGFR-2 or inhibition of VEGFR-2 tyrosine kinase activity abolishes P2Y(2)R-mediated VCAM-1 expression. Furthermore, VEGFR-2 and the P2Y(2)R co-localize upon UTP stimulation. Deletion or mutation of two Src homology-3-binding sites in the C-terminal tail of the P2Y(2)R or inhibition of Src kinase activity abolished the P2Y(2)R-mediated transactivation of VEGFR-2 and subsequently inhibited UTP-induced VCAM-1 expression. Moreover, activation of VEGFR-2 by UTP leads to the phosphorylation of Vav2, a guanine nucleotide exchange factor for Rho family GTPases. Using a binding assay to measure the activity of the small GTPases Rho, we found that stimulation of HCAEC by UTP increased the activity of RhoA and Rac1 (but not Cdc42). Significantly, a dominant negative form of RhoA inhibited P2Y(2)R-mediated VCAM-1 expression, whereas expression of dominant negative forms of Cdc42 and Rac1 had no effect. These data indicate a novel mechanism whereby a nucleotide receptor transactivates a receptor tyrosine kinase to generate an inflammatory response associated with atherosclerosis.
...
PMID:The P2Y2 nucleotide receptor mediates vascular cell adhesion molecule-1 expression through interaction with VEGF receptor-2 (KDR/Flk-1). 1517 47

The flow-responsive transcription factor KLF2 is acquiring a leading role in the regulation of endothelial cell gene expression. A genome-wide microarray expression profiling is described employing lentivirus-mediated, 7-day overexpression of human KLF2 at levels observed under prolonged flow. KLF2 is not involved in lineage typing, as 42 endothelial-specific markers were unaffected. Rather, KLF2 generates a gene transcription profile (> 1000 genes) affecting key functional pathways such as cell migration, vasomotor function, inflammation, and hemostasis and induces a morphology change typical for shear exposure including stress fiber formation. Protein levels for thrombomodulin, endothelial nitric oxide synthase, and plasminogen activator inhibitor type-1 are altered to atheroprotective levels, even in the presence of the inflammatory cytokine TNF-alpha. KLF2 attenuates cell migration by affecting multiple genes including VEGFR2 and the potent antimigratory SEMA3F. The distribution of Weibel-Palade bodies in cultured cell populations is normalized at the single-cell level without interfering with their regulated, RalA-dependent release. In contrast, thrombin-induced release of Weibel-Palade bodies is significantly attenuated, consistent with the proposed role of VWF release at low-shear stress regions of the vasculature in atherosclerosis. These results establish that KLF2 acts as a central transcriptional switch point between the quiescent and activated states of the adult endothelial cell.
...
PMID:KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. 1645 54

Angiogenesis, a process of new blood vessel formation, is a key process involved in normal development and wound repair as well as in the various pathophysiologies such as ischemic heart and limb diseases and atherosclerosis. Reactive oxygen species (ROS) such as superoxide and H(2)O(2) function as signaling molecules in many aspects of growth factor-mediated responses including angiogenesis. Vascular endothelial growth factor (VEGF) is a key angiogenic growth factor and stimulates proliferation, migration, and tube formation of endothelial cells (ECs) primarily through the VEGF receptor type2 (VEGR2, KDR/Flk1). VEGF binding initiates autophosphorylation of VEGFR2, which results in activation of downstream signaling enzymes including ERK1/2, Akt, and eNOS in ECs, thereby stimulating angiogenesis. The major source of ROS in EC is a NADPH oxidase which consists of Nox1, Nox2 (gp91phox), Nox4, p22phox, p47phox, p67phox and the small G protein Rac1. The endothelial NADPH oxidase is activated by angiogenic factors including VEGF and angiopoietin-1. ROS derived from this enzyme stimulate diverse redox signaling pathways leading to angiogenesis-related gene induction as well as EC migration and proliferation, which may contribute to postnatal angiogenesis in vivo. The aim of this review is to provide an overview of the recent progress on the emerging area of the role of ROS derived from NADPH oxidase and redox signaling in angiogenesis. Understanding these mechanisms may provide insight into the NADPH oxidase and redox signaling components as potential therapeutic targets for treatment of angiogenesis-dependent cardiovascular diseases and for promoting angiogenesis in ischemic limb and heart diseases.
...
PMID:Redox signaling in angiogenesis: role of NADPH oxidase. 1678 92

PPAR-gamma agonists (thiazolidinediones, TZDs) may improve endothelial function independently of insulin sensitizing. Bone marrow-derived endothelial progenitor cells (EPC) contribute to neoangiogenesis. Mice were treated with pioglitazone, 20mg/kg/day for 10 days. Treatment with TZD upregulated circulating Sca-1/VEGFR-2 positive EPC in the blood (235+/-60%) and the bone marrow (166+/-30%), cultured spleen-derived DiLDL/lectin positive EPC increased to 231+/-21% (n=24 per group). Upregulation of EPC was persistent after 20 days. TZD increased SDF-1-induced migratory capacity per number of EPC by 246+/-73% and increased expression of telomere repeat-binding factor 2 by 320+/-50%. In vivo neoangiogenesis was increased two-fold (214+/-42%, 20 days). The NOS inhibitor L-NAME did not inhibit the TZD-induced upregulation of EPC. EPC from TZD-treated animals showed reduced in vivo apoptosis (65+/-2.8% of vehicle). In cultured human EPC, pre-treatment with pioglitazone prevented H(2)O(2)-induced apoptosis. Inhibition of EPC apoptosis by TZD was abolished in the presence of wortmannin but not by LNMA. In summary, TZD upregulates both number and functional capacity of endothelial progenitor cells. Pioglitazone prevents apoptosis of EPC in mice as well as in human EPC in a PI3K-dependent but NO-independent manner. Reduction of EPC apoptosis by TZD may be a potentially beneficial mechanism for patients with vascular diseases.
Atherosclerosis 2007 May
PMID:The PPAR-gamma agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells. 1687 72

Plaque angiogenesis may be associated with the development of unstable and vulnerable plaques. Vascular endothelial growth factors (VEGFs) are potent angiogenic factors that can affect plaque neovascularization. Our objective was to determine the effect of diabetes on atherosclerosis and on the expression of angiogenesis-related genes in atherosclerotic lesions. Alloxan was used to induce diabetes in male Watanabe heritable hyperlipidemic (WHHL) rabbits that were sacrificed 2 and 6 months after the induction of diabetes. Nondiabetic WHHL rabbits served as controls. Blood glucose (Glc), serum-free fatty acids (FFA), and serum triglyceride levels were significantly higher in diabetic rabbits. Accelerated atherogenesis was observed in the diabetic WHHL rabbits together with increased intramyocellular lipids (IMCL), as determined by 1H-NMR spectroscopy. Atherosclerotic lesions in the diabetic rabbits had an increased content of macrophages and showed significant increases in immunostainings for vascular endothelial growth factor (VEGF)-A, VEGF-D, VEGF receptor-1, VEGF receptor-2, RAGE, and NF-kappaB. VEGF-A165 and VEGFR-2 mRNA levels were significantly increased in aortas of the diabetic rabbits, where a trend toward increased plaque vascularization was also observed. These results suggest that diabetes accelerates atherogenesis, up-regulates VEGF-A, VEGF-D, and VEGF receptor-2 expression, and increases NF-kappaB, RAGE, and inflammatory responses in atherosclerotic lesions in WHHL rabbits.
...
PMID:VEGF-A, VEGF-D, VEGF receptor-1, VEGF receptor-2, NF-kappaB, and RAGE in atherosclerotic lesions of diabetic Watanabe heritable hyperlipidemic rabbits. 1693 42

Wogonin, one of flavonoid derived from particular plants, enriches the property of anti-inflammation. Inflammation-stimulated angiogenesis plays an important role in many pathological diseases, such as rheumatoid arthritis, atherosclerosis, and cancer. The aim of this study was to investigate the suppressive effect of wogonin on lipopolysaccharide (LPS)-induced angiogenesis in human umbilical endothelial cell (HUVEC) cultures. By cell differentiation assays, migration and tube formation activity under LPS treatment were evaluated. Besides, IL-6 neutralizing antibody was added to test the inhibitory effect in the phenotypic alteration. Western blot analysis, ELISA cytokine assay, and quantitative real time-PCR were performed for VEGF, IL-6, VEGF receptors, and IL-6 receptor gene expressions on HUVEC with wogonin treatment. Furthermore, in vivo chorioallantoic membrane (CAM) assay was applied to evaluate the percentage of new vessels formation. The results revealed that wogonin (10(-8)-10(-5) M) inhibited LPS-induced angiogenesis in a concentration-dependent manner. The mRNA and protein expressions of VEGF, VEGFR-2, IL-6, and sIL-6Ralpha were attenuated (P<0.05), but not VEGFR-1. In the LPS-induced CAM model, our data suggested that wogonin (10(-8)-10(-5) M) significantly decreased new vessel formation and vascular network (P<0.05). We conclude that wogonin suppresses both in vitro and in vivo LPS-induced angiogenesis, through VEGFR-2, but not VEGFR-1.
...
PMID:Protective role of wogonin against lipopolysaccharide-induced angiogenesis via VEGFR-2, not VEGFR-1. 1697 23

Vascular endothelial growth factor receptor-1 (VEGFR-1) is a member of the VEGFR family, and binds VEGF-A, PlGF, and VEGF-B. An important feature of VEGFR-1 is that, unlike other VEGFR genes, it expresses two types of mRNA, one for a full-length receptor and another for a soluble short protein known as soluble VEGFR-1 (sFlt-1). The binding-affinity of VEGFR-1 for VEGF-A is one order of magnitude higher than that of VEGFR-2, whereas the kinase activity of VEGFR-1 is about 10-fold weaker than that of VEGFR-2. Through its ligand-binding region and by trapping ligands, VEGFR-1 plays a negative role in angiogenesis at embryogenesis. In adulthood, however, VEGFR-1 is expressed not only on endothelial cells but also on macrophages, and promotes the function of macrophages, inflammatory diseases, cancer metastasis, and atherosclerosis via its kinase activity. Soluble VEGFR-1 is abnormally overexpressed in the placenta of preeclamptic patients, and suggested to cause the major pathological symptoms on the maternal side such as hypertension and renal dysfunction, most likely by blocking the physiological VEGF-A. VEGFR-1 including its soluble form is involved in a variety of human illnesses, making it an important target in the development of new strategies to suppress disease.
...
PMID:Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. 1710 93


1 2 3 4 5 Next >>

---