Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

VEGF-A induces angiogenesis and regulates endothelial function via production and release of nitric oxide (NO), which is produced by endothelial nitric oxide synthase (eNOS). While the upregulation of eNOS expression has been shown to be mediated via VEGF receptor KDR, there is controversy about which of the VEGF receptors triggers the release of nitric oxide in endothelial cells. In order to determine the levels of NO produced in response to VEGF-A stimulation in different endothelial cells, a reporter assay measuring the formation of cGMP as the direct product of NO-induced activation of guanylate cyclase was performed. Using two independent experimental strategies, we were able to prove that VEGF receptor KDR, but not VEGF receptor Flt-1, can induce NO release in endothelial cells. First, we made use of porcine aortic endothelial cells (PAE) expressing either KDR or Flt-1. While KDR-expressing PAE/KDR cells responded to VEGF-A stimulation with a significant elevation of intracellular cGMP already after 2 min, Flt-1-expressing PAE/Flt-1 cells did not show any signal in this RIA-based cGMP assay. In a second experimental strategy freshly isolated human umbilical vein endothelial cells (HUVEC) were stimulated either with the KDR-specific ligand VEGF-E or with the Flt-1-specific ligand PIGF-2. VEGF-E induces cGMP elevation in this setting, while PIGF-2 was unable to do so, clearly demonstrating that KDR is responsible for NO release in endothelial cells. In our assays cGMP formation is fully dependent on NO generation since the NOS inhibitor L-NAME can block this VEGF-A-induced action. These data show that the VEGF receptor KDR is responsible for NO release in endothelial cells, highlighting a new function of KDR and further supporting the importance of KDR in the regulation of the vasculature.
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PMID:A novel function of VEGF receptor-2 (KDR): rapid release of nitric oxide in response to VEGF-A stimulation in endothelial cells. 1060 Apr 73

Endostatin was suggested to be an antiangiogenic agent with the potential for clinical use in cancer therapy. Unfortunately, up to now no antiangiogenic effect was seen in clinical trials using this substance. The lack of response might be caused by an incomplete understanding of endostatin signaling. Endostatin is known to influence the vascular endothelial growth factor (VEGF) signaling pathway. It has been reported to bind to the VEGF receptor KDR directly and to decrease the phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 via the protein phosphatase 2A (PP2A). But so far no details of endostatin signaling with regard to NO downstream effectors have been revealed. In the present work the authors demonstrate that endostatin down-regulates the protein level of soluble guanylate cyclase (sGC) in endothelial cells of newly formed blood vessels in 5 day-old wounds (control: 62.5 +/- 33 vessels/mm2, endostatin: 9.2 +/- 3.2 vessels/mm2). This was confirmed in experiments with endothelial tubes of embryoid bodies and endothelial cells derived from embryonic stem cells (eESCs; control: 126 +/- 20, endostatin: 58 +/- 10). The decrease of sGC protein levels in response to endostatin was abolished after preincubation with the PP2A inhibitor okadaic acid. No alterations of sGC mRNA levels could be found under endostatin treatment in eESC. The authors conclude that endostatin affects VEGF signaling in endothelial cells by a post-transcriptional PP2A-dependent down-regulation of sGC protein levels.
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PMID:Endostatin down-regulates soluble guanylate cyclase (sGC) in endothelial cells in vivo: influence of endostatin on vascular endothelial growth factor (VEGF) signaling. 1641 Feb 24

Vascular endothelial growth factor-A (VEGF), which binds to both VEGF receptor-1 (Flt1) and VEGFR-2 (KDR/Flk-1), requires nitric oxide (NO) to induce angiogenesis in a cGMP-dependent manner. Here we show that VEGF-E, a VEGFR-2-selective ligand stimulates NO release and tube formation in human umbilical vein endothelial cells (HUVEC). Inhibition of phospholipase Cgamma (PLCgamma) with U73122 abrogated VEGF-E induced endothelial cell migration, tube formation and NO release. Inhibition of endothelial nitric oxide synthase (eNOS) using l-NNA blocked VEGF-E-induced NO release and angiogenesis. Pre-incubation of HUVEC with the soluble guanylate cyclase inhibitor, ODQ, or the protein kinase G (PKG) inhibitor, KT-5823, had no effect on angiogenesis suggesting that the action of VEGF-E is cGMP-independent. Our data provide the first demonstration that VEGFR-2-mediated NO signaling and subsequent angiogenesis is through a mechanism that is dependent on PLCgamma but independent of cGMP and PKG.
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PMID:VEGF-E activates endothelial nitric oxide synthase to induce angiogenesis via cGMP and PKG-independent pathways. 1672 9

To evaluate the estrogenic potential of the phytoestrogen secoisolariciresinol diglycoside (SDG) found in linseed meal (LSM) on jejunal mass, cellular proliferation, vascularity, and expression of angiogenic factors and their receptors, 48 ovariectomized ewes (54.6 +/- 1.1 kg) were fed a diet containing 12.5% LSM for 0, 1, 7, or 14 d and implanted with estradiol-17beta (E(2)) for 0, 6, or 24 h before tissue collection. Angiogenic factors and receptors measured included vascular endothelial growth factor (VEGF), VEGF receptor-1 (FLT), VEGF receptor-2 (KDR), fibroblast growth factor (FGF), FGF receptor 2 IIIc (FGFR), angiopoietin (ANG)-1, ANG-2, ANG receptor (Tie-2), endothelial nitric oxide synthase (eNOS), and soluble guanylate cyclase (sGC). There was a LSM x E(2) interaction (P = 0.003) on the jejunal cellular proliferation index. Jejunal cellular proliferation increased (P < 0.002) in ewes not fed LSM and implanted with E(2) for 6 or 24 h compared with ewes implanted for 0 h but did not increase when LSM was fed for 1, 7, or 14 d. Neither feeding LSM nor implanting ewes with E(2) altered vascular area density (P > 0.75) or vascular surface area (P > 0.29) of the jejunal villi. Expression of mRNA for the angiogenic factors VEGF, FGF, FGFR, ANG-1, ANG-2, and Tie-2 were not altered (P > 0.33) by feeding LSM or implanting ewes with E(2). Implanting ewes with E(2) for 6 h increased (P = 0.04) eNOS expression compared with ewes implanted for 0 h. Feeding LSM and implanting ewes with E(2) interacted to alter mRNA expression of FLT (P = 0.04), KDR (P < 0.001), and sGC (P = 0.04). When LSM was fed for 1, but not 0, 7, or 14 d, expression of FLT mRNA decreased (P < 0.03) when ewes were implanted with E(2) for 24 h compared with ewes implanted for 0 or 6 h. Expression of KDR mRNA was suppressed in ewes fed LSM for 1 (P = 0.03) or 7 d (P = 0.0007) and implanted with E(2) for 24 h compared with ewes implanted for 0 h. When LSM was fed for 14 d, implanting ewes for 6 h increased (P = 0.04) KDR expression compared with ewes implanted for 0 h. Ewes fed LSM for 0 and 1 d experienced an increase in sGC mRNA expression when implanted for 6 h (P = 0.001) compared with ewes implanted for 0 h. When implanted for 24 h, levels were similar (P = 0.80) to those observed when ewes were implanted for 0 h. Expression of sGC was not altered by E(2) when LSM was fed for 1, 7, or 14 d (P > 0.11). The impacts of E(2) and LSM on nutrient uptake and growth during physiologically important time points are unknown.
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PMID:Impacts of linseed meal and estradiol-17beta on mass, cellularity, angiogenic factors, and vascularity of the jejunum. 1856 19