P2Y Receptor-Mediated Ca2+ Signaling Increases Human Vascular Endothelial Cell Permeability

Tanaka, Naoko; Kawasaki, Kyozi; Nejime, Namie; Kubota, Yōko; Nakamura, Kazuki; Kunitomo, Masaru; Takahashi, Kyoko; Hashimoto, Michio; Shinozuka, Kazumasa

doi:10.1254/jphs.fpj03036x

Cited by 40 publications

(27 citation statements)

References 25 publications

(16 reference statements)

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“…Extracellular NDPK in the tumour vasculature would elevate nucleotide signalling and subsequent release of vasoactive factors with angiogenic effects (Ziche and Morbidelli, 2000). In support of our hypothesis, a positive correlation between the regulation of P2Y signalling and various angiogenic properties (Moser et al, 2001;Tanaka et al, 2004;Kaczmarek et al, 2005) is known.…”

Section: Discussionsupporting

confidence: 75%

Purinergic regulation of angiogenesis by human breast carcinoma-secreted nucleoside diphosphate kinase

et al. 2007

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MDA-MB-435S human breast cancer cells (435S) secrete nucleoside diphosphate kinase (NDPK) that supports metastases and is inhibited by epigallocatechin gallate (EGCG) and ellagic acid (EA). We hypothesise that 435S cell-secreted NDPK-B supports tumour formation by modulating ATP levels locally to activate endothelial cell (EC) P2Y receptor-mediated angiogenesis. Epigallocatechin gallate (IC 50 ¼ 8-10 mM) and EA (IC 50 ¼ 2-3 mM) suppressed 435S cell growth, but had less effect on human CD31 þ EC growth. Epigallocatechin gallate (IC 50 ¼ 11 mM) and EA (IC 50 ¼ 1 mM) also prevented CD31 þ EC tubulogenesis on Matrigelt. 435S cellconditioned media induced tubulogenesis in a cell number, time, and nucleotide-dependent manner. Ellagic acid (1 mM), but not equimolar EGCG, reduced cell number-dependent angiogenesis. P2Y 1 receptor activation by NDPK-generated nucleotide (100 mM ATP) or by 10 mM 2-methyl-thio-ATP (2MS-ATP) promoted tubulogenesis on collagen and was blocked by the P2Y 1 antagonist MRS2179 (10 mM). Physiological amounts of purified as well as 435S cell-secreted NDPK also promoted angiogenesis that was attenuated by NDPK depletion or 10 mM MRS2179, indicating a P2Y 1 receptor-mediated pathway. These results support the notion that secreted NDPK mediates angiogenesis via P2Y receptor signalling and suggests that novel inhibitors of NDPK may be useful as therapeutics.

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Section: Discussionsupporting

confidence: 75%

Purinergic regulation of angiogenesis by human breast carcinoma-secreted nucleoside diphosphate kinase

et al. 2007

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“…Because 2-APB has been observed to interfere with store-operated Ca 2+ entry [25,51] , this mechanism is not required. However, 2-Me-S-ADPinduced contraction, but not α,β-Me-ATP-induced contraction, was sensitive to U73122, indicating a potential role for PLC and subsequent intracellular Ca 2+ signaling in mediating P2Y purinergic contraction for both motility responses, confirming previous reports [52,53] . In contrast, contraction induced by either agonist was abolished by co-application of the SERCA inhibitor thapsigargin and the L-type Ca 2+ channel blocker verapamil.…”

Section: Intracellular Signaling Cascade Following Purinergic Receptosupporting

confidence: 87%

P2Y receptor-mediated transient relaxation of rat longitudinal ileum preparations involves phospholipase C activation, intracellular Ca2+ release and SK channel activation

et al. 2016

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Aim: Purinergic signaling plays a major role in the enteric nervous system, where it governs gut motility through a number of P2X and P2Y receptors. The aim of this study was to investigate the P2Y receptor-mediated motility in rat longitudinal ileum preparations. Methods: Ileum smooth muscle strips were prepared from rats, and fixed in an organ bath. Isometric contraction and relaxation responses of the muscle strips were measured with force transducers. Drugs were applied by adding of stock solutions to the organ bath to yield the individual final concentrations. Results: Application of the non-hydrolyzable P2 receptor agonists α,β-Me-ATP or 2-Me-S-ADP (10, 100 µmol/L) dose-dependently elicited a transient relaxation response followed by a sustained contraction. The relaxation response was largely blocked by SK channel blockers apamin (500 nmol/L) and UCL1684 (10 µmol/L), PLC inhibitor U73122 (100 µmol/L), IP 3 receptor blocker 2-APB (100 µmol/L) or sarcoendoplasmic Ca 2+ ATPase inhibitor thapsigargin (1 µmol/L), but not affected by atropine, NO synthase blocker L-NAME or tetrodotoxin. Furthermore, α,β-Me-ATP-induced relaxation was suppressed by P2Y 1 receptor antagonist MRS2179 (50 µmol/L) or P2Y 13 receptor antagonist MRS2211 (100 µmol/L), and was abolished by co-application of the two antagonists, whereas 2-Me-S-ADP-induced relaxation was abolished by P2Y 6 receptor antagonist MRS2578 (50 µmol/L). In addition, P2Y 1 receptor antagonist MRS2500 (1 µmol/L) not only abolished α,β-Me-ATP-induced relaxation, but also suppressed 2-Me-S-ADP-induced relaxation. Conclusion: P2Y receptor agonist-induced transient relaxation of rat ileum smooth muscle strips is mediated predominantly by P2Y 1 receptor, but also by P2Y 6 and P2Y 13 receptors, and involves PLC, IP 3 , Ca 2+ release and SK channel activation, but is independent of acetylcholine and NO release.

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“…A trophic role for P2Y receptors was suggested when it was proposed that the size of endothelial cells is regulated by P2Y receptors (Tanaka et al, 2003(Tanaka et al, , 2004. A comparative study of P2Y receptor endotheliummediated responses of single endothelial cells from bovine retina and HUVECs showed different patterns of P2Y 2 receptor desensitization and roles of growth factors (Sanabria et al, 2008).…”

Section: Purinergic Signaling and Blood Vesselsmentioning

confidence: 99%

Purinergic Signaling and Blood Vessels in Health and Disease

2013

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P2Y Receptor-Mediated Ca2+ Signaling Increases Human Vascular Endothelial Cell Permeability

Cited by 40 publications

References 25 publications

Purinergic regulation of angiogenesis by human breast carcinoma-secreted nucleoside diphosphate kinase

Purinergic regulation of angiogenesis by human breast carcinoma-secreted nucleoside diphosphate kinase

P2Y receptor-mediated transient relaxation of rat longitudinal ileum preparations involves phospholipase C activation, intracellular Ca2+ release and SK channel activation

Purinergic Signaling and Blood Vessels in Health and Disease

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