Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice

Yamamoto, Kimiko; Sokabe, Takaaki; Μatsumoto, Takahiro; Yoshimura, Kimihiro; Shibata, Masahiro; Ohura, Norihiko; Fukuda, Tsuyoshi; Satō, Takashi; Sekine, Keisuke; Kato, Shigeaki; Isshiki, Masashi; Fujita, Toshiro; Kobayashi, Mikio; Kawamura, Koichi; Masuda, Hirotake; Kamiya, Akira; Ando, Jun

doi:10.1038/nm1338

Cited by 319 publications

(256 citation statements)

References 26 publications

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“…This indicates that ATP and P2 receptors may be of importance for shear stress-mediated effects which is in agreement with the well-established release of ATP from endothelial cells during shear stress [82]. Vessel dilation induced by acute increases in blood flow is markedly suppressed in P2X 4 −/−mice, indicating that endothelial P2X 4 channels are crucial to flow-sensitive mechanisms that regulate blood pressure and vascular remodeling [83]. The importance of the presence of ATP for flow-induced vasodilation has been confirmed in rat mesenteric arteries [84].…”

Section: Direction and Mechanism Of The Endothelial Flow Responsesupporting

confidence: 85%

“…Interestingly, the effect of ATP could be mimicked by UTP, indicating that P2Y receptors could be of similar importance as the P2X 4 receptor for shear-induced vasodilatation. P2X 4 −/− mice have higher blood pressure and excrete smaller amounts of NO products in their urine than do wild-type mice [83].…”

Section: Direction and Mechanism Of The Endothelial Flow Responsementioning

confidence: 94%

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The touching story of purinergic signaling in epithelial and endothelial cells

Öhman

Erlinge

2012

Purinergic Signalling

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Endothelial and epithelial cells have something in commonthey are both the barrier and bridge between different environments. Forming a one-cell layer lining of blood vessels, airways, and urinary tract, they are in constant contact with a wide variety of cells, putting high demands on the communication skills of these cells. The purinergic signaling system offers a dynamic and versatile way for local and rapid intercellular communication and involves three processes: nucleotide release, enzymatic degradation, and activation of purinergic receptors. With an impressive number of molecular members of the system (15 P2 receptor subtypes and in total 16 nucleotide-degrading enzymes), cells have managed to put purines and pyrimidines as well as their derivatives to use in an array of different areas, including regulation of flow, secretion, and vascular tone. Indeed, the purinergic signaling system is an ancient way of intercellular communication that most likely could be found in the first most primitive life form [1]. The scope of this review is to give an overview of exciting features of purinergic signaling and examples of gaps to fill in understanding its role in the cells lining the body-the endothelium and the epithelium. Purinergic signaling-an overviewExtracellular nucleotides exert their paracrine signaling by binding to P2 receptors present at the cell surface. The P2 receptor family is divided into two groups: P2X receptors, which are ligand-activated ion channels, and P2Y receptors, which are G protein-coupled receptors (reviewed in [2]). Each receptor is characterized by its affinity pattern for different nucleotides and different cell types display varying receptor profiles. While P2X receptors respond only to ATP, P2Y receptors can be activated by other nucleotides such as ADP, UTP, and UDP. Extracellular nucleotide concentrations are precisely regulated by ecto-enzymes, which cleave nucleotide tri-/diphosphates. The result of signaling by the extracellular nucleotides ATP/ADP, UTP/UDP and the nucleoside adenosine is both acute, for example the rapid platelet aggregation induced by ADP, and chronic, via changes in gene expression induced by P2 receptor stimulation. Ligand availability for P2 receptors is regulated by a group of enzymes termed ectonucleotidases. NTPDase1 (apyrase; CD39) cleaves ATP to AMP, NTPDase2 (CD39L1) cleaves ATP to ADP, and 5′-ectonucleotidase (CD73) generates adenosine from AMP. Adenosine is the end product of purinergic signaling, acting on adenosine receptors (A1, A2a, A2b, and A3; also termed P1 receptors) or recycling by the cell after reuptake through the equilibrating nucleoside transporters ENT1 and 2. UTP is believed to be released simultaneously with ATP via the same mechanism but at a lower concentration (UTP/ATP, 1:10-100). UTP is degraded in the same way as ATP, but the biological function of uridine is poorly understood and no uridine receptor has been identified. Figure 1 shows an outline of nucleotide metabolism. Purinergic toneAll investigators that have tried t...

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Section: Direction and Mechanism Of The Endothelial Flow Responsesupporting

confidence: 85%

Section: Direction and Mechanism Of The Endothelial Flow Responsementioning

confidence: 94%

The touching story of purinergic signaling in epithelial and endothelial cells

Öhman

Erlinge

2012

Purinergic Signalling

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“…In this model, released nucleotides bind to endothelial P2 receptors, triggering NO release and subsequent smooth muscle relaxation. A recent study has highlighted the critical role of endothelial P2X 4 receptors in flow-induced vasodilation [129]. In mice lacking P2X 4 receptors, flowinduced increases of [Ca 2+ ] i in the endothelial cells were absent, as was the endothelium-dependent vascular dilatation.…”

Section: Mechanically Released Nucleotidesmentioning

confidence: 99%

ATP release from non-excitable cells

Praetorius

Leipziger

2009

Purinergic Signalling

207

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All cells release nucleotides and are in one way or another involved in local autocrine and paracrine regulation of organ function via stimulation of purinergic receptors. Significant technical advances have been made in recent years to quantify more precisely resting and stimulated adenosine triphosphate (ATP) concentrations in close proximity to the plasma membrane. These technical advances are reviewed here. However, the mechanisms by which cells release ATP continue to be enigmatic. The current state of knowledge on different suggested mechanisms is also reviewed. Current evidence suggests that two separate regulated modes of ATP release co-exist in nonexcitable cells: (1) a conductive pore which in several systems has been found to be the channel pannexin 1 and (2) vesicular release. Modes of stimulation of ATP release are reviewed and indicate that both subtle mechanical stimulation and agonist-triggered release play pivotal roles. The mechano-sensor for ATP release is not yet defined.

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“…In P2X4-knockout mice, shear stress did not induce Ca 2+ signaling and the release of NO from the vascular endothe lial cells decreased, resulting in hypertension, impaired vasodilatory responses (following increased tissue blood flow) and vascular remodeling (change in diameter) following changes in blood flow. [10]. Thus, shear stress plays an important role in maintaining normal functions of the circulation system.…”

Section: Ca 2+ Signaling and Regulation Of Circulationmentioning

confidence: 99%