Vasodilatation of intrapulmonary arteries to P2‐receptor nucleotides in normal and pulmonary hypertensive newborn piglets

McMillan, Merlin; Burnstock, Geoffrey; Haworth, Sheila G.

doi:10.1038/sj.bjp.0702815

Cited by 26 publications

(15 citation statements)

References 37 publications

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“…Third, ATP could also induce vasodilation via P 2Y receptors located on the smooth muscle cells, an effect that may not require the formation of vasodilators. This is supported by some in vitro studies indi- cating that ATP exerts vasodilation partially via endotheliumindependent mechanisms (26,28). Fourth, ATP-induced vasodilation may be endothelium-derived hyperpolarizing factor (EDHF) dependent.…”

Section: Discussionmentioning

confidence: 57%

ATP-induced vasodilation and purinergic receptors in the human leg: roles of nitric oxide, prostaglandins, and adenosine

Mortensen¹,

González‐Alonso²,

Bune³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

106

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Mortensen SP, Gonzá lez-Alonso J, Bune LT, Saltin B, Pilegaard H, Hellsten Y. ATP-induced vasodilation and purinergic receptors in the human leg: roles of nitric oxide, prostaglandins, and adenosine. Am J Physiol Regul Integr Comp Physiol 296: R1140 -R1148, 2009. First published December 31, 2008 doi:10.1152/ajpregu.90822.2008.-Plasma ATP is thought to contribute to the local regulation of skeletal muscle blood flow. Intravascular ATP infusion can induce profound limb muscle vasodilatation, but the purinergic receptors and downstream signals involved in this response remain unclear. This study investigated: 1) the role of nitric oxide (NO), prostaglandins, and adenosine as mediators of ATP-induced limb vasodilation and 2) the expression and distribution of purinergic P 2 receptors in human skeletal muscle. Systemic and leg hemodynamics were measured before and during 5-7 min of femoral intra-arterial infusion of ATP [0.45-2.45 mol/min] in 19 healthy male subjects with and without coinfusion of N G -monomethyl-L-arginine (L-NMMA; NO formation inhibitor; 12.3 Ϯ 0.3 (SE) mg/min), indomethacin (INDO; prostaglandin formation blocker; 613 Ϯ 12 g/ min), and/or theophylline (adenosine receptor blocker; 400 Ϯ 26 mg). During control conditions, ATP infusion increased leg blood flow (LBF) from baseline conditions by 1.82 Ϯ 0.14 l/min. When ATP was coinfused with either L-NMMA, INDO, or L-NMMA ϩ INDO combined, the increase in LBF was reduced by 14 Ϯ 6, 15 Ϯ 9, and 39 Ϯ 8%, respectively (all P Ͻ 0.05), and was associated with a parallel lowering in leg vascular conductance and cardiac output and a compensatory increase in leg O 2 extraction. Infusion of theophylline did not alter the ATP-induced leg hyperemia or systemic variables. Real-time PCR analysis of the mRNA content from the vastus lateralis muscle of eight subjects showed the highest expression of P2Y2 receptors of the 10 investigated P2 receptor subtypes. Immunohistochemistry showed that P2Y2 receptors were located in the endothelium of microvessels and smooth muscle cells, whereas P2X1 receptors were located in the endothelium and the sacrolemma. Collectively, these results indicate that NO and prostaglandins, but not adenosine, play a role in ATP-induced vasodilation in human skeletal muscle. The expression and localization of the nucleotide selective P2Y2 and P2X1 receptors suggest that these receptors may mediate ATP-induced vasodilation in skeletal muscle. skeletal muscle; adenosine 5Ј-triphosphate; purinergic receptors; nitric oxide; prostaglandins SKELETAL MUSCLE BLOOD FLOW is closely regulated to match O 2 delivery to the metabolic demand of contracting myocytes during a wide array of exercise modalities (2,15,29,42). The precise regulation of muscle blood flow is believed to mainly be the result of the competing influences of locally released vasodilator signals and sympathetic neural vasoconstrictor activity (9). Previous reports employing double blockade of nitric oxide synthase (NOS) and cyclooxygenase (COX) by which nitric oxide (NO) and prostaglindi...

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Section: Discussionmentioning

confidence: 57%

ATP-induced vasodilation and purinergic receptors in the human leg: roles of nitric oxide, prostaglandins, and adenosine

Mortensen¹,

González‐Alonso²,

Bune³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

106

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“…The discovery of ATP as an endogenous activator of TRPV4‐eNOS signaling may be a crucial step towards deciphering the physiological and pathological roles of TRPV4 channels in the pulmonary circulation. Purinergic signaling is an essential component to the pulmonary vasculature,59, 60, 61, 62, 63 and ATP activation of TRPV4 channels represents a mechanism that may link physiological stimuli to the regulation of pulmonary vascular function. ATP can be released from sympathetic nerves during synaptic transmission, or can be released into the circulation by ECs, SMCs, or erythrocytes 25, 26, 64, 65.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide–Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries

Marziano

Hong

Cope

et al. 2017

JAHA

132

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BackgroundRecent studies demonstrate that spatially restricted, local Ca2+ signals are key regulators of endothelium‐dependent vasodilation in systemic circulation. There are drastic functional differences between pulmonary arteries (PAs) and systemic arteries, but the local Ca2+ signals that control endothelium‐dependent vasodilation of PAs are not known. Localized, unitary Ca2+ influx events through transient receptor potential vanilloid 4 (TRPV4) channels, termed TRPV4 sparklets, regulate endothelium‐dependent vasodilation in resistance‐sized mesenteric arteries via activation of Ca2+‐dependent K+ channels. The objective of this study was to determine the unique functional roles, signaling targets, and endogenous regulators of TRPV4 sparklets in resistance‐sized PAs.Methods and ResultsUsing confocal imaging, custom image analysis, and pressure myography in fourth‐order PAs in conjunction with knockout mouse models, we report a novel Ca2+ signaling mechanism that regulates endothelium‐dependent vasodilation in resistance‐sized PAs. TRPV4 sparklets exhibit distinct spatial localization in PAs when compared with mesenteric arteries, and preferentially activate endothelial nitric oxide synthase (eNOS). Nitric oxide released by TRPV4‐endothelial nitric oxide synthase signaling not only promotes vasodilation, but also initiates a guanylyl cyclase‐protein kinase G‐dependent negative feedback loop that inhibits cooperative openings of TRPV4 channels, thus limiting sparklet activity. Moreover, we discovered that adenosine triphosphate dilates PAs through a P2 purinergic receptor‐dependent activation of TRPV4 sparklets.ConclusionsOur results reveal a spatially distinct TRPV4‐endothelial nitric oxide synthase signaling mechanism and its novel endogenous regulators in resistance‐sized PAs.

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“…They also described endothelial cells as a rich source of ATP, released both under basal and stimulated conditions (13), and mediating autocrine and/or paracrine signaling events in cells that also express purinergic receptors. ATP released from nerve cells and endothelial cells may modulate vascular tone (43). In addition, extracellular ATP may influence migration, proliferation and death of vascular smooth muscle cells and endothelial cells (44).…”

Section: Discussionmentioning

confidence: 99%

Extracellular ATP-mediated Signaling for Survival in Hyperoxia-induced Oxidative Stress

Ahmad

Ghosh

et al. 2004

Journal of Biological Chemistry

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Cells release ATP either under basal conditions or in response to stress or certain stimuli (1, 2). Mechanical stress, hypotonic media, vasoactive agents, inflammation, cAMP and ATP itself can stimulate ATP release from cells (3). Extracellular ATP binds to specific plasma membrane receptors called P2 receptors. Depending on the cell type, binding of ATP to its receptors can initiate important signaling events like (i) increases in intracellular calcium; (ii) activation of phospholipases; (iii) modulation of cell volume; (iv) inhibition of platelet aggregation; (v) alteration of vascular tone; (vi) neurotransmission; (vii) elevation of cardiac/skeletal muscle contractility; (viii) immune cell activation; (ix) increased ciliary beat frequency and mucus secretion; and (x) enhanced cell growth and proliferation (3). Although routes of ATP release are not well defined, cytolysis, vesicle-mediated ATP release, and ATP release via channels like ATP-binding cassette (ABC) proteins and connexin hemichannels may contribute (1, 4).The role of ATP release in oxidative stress is not clear. Severe oxidative stress can diminish intracellular ATP (5, 6). Delayed catabolism of extracellular nucleotides due to diminished ectonucleotidase activity in the presence of reactive oxygen species (ROS) 1 also has been suggested (7). Whether extracellular ATP release occurs due to oxidative stresses like hyperoxia, and what the functional significance of this process could be is unknown. Microvascular endothelial cells are primary targets of hyperoxic lung injury (8) and in other forms of acute respiratory failure. Hypoxic preexposure of human lung microvascular endothelial cells (HLMVEC) attenuates cell death caused by subsequent hyperoxic exposure (9). This is partially attributed to up-regulation of PI 3-kinase (PI3K), a component of an established cell survival pathway. Previously we showed that hypoxic (1 or 3% O 2 ) exposure induces ATP release in HLMVEC and fetal lung fibroblasts (10). There, hypoxia and ATP act synergistically to upregulate common proliferation-inducing pathways in fibroblasts. Extracellular ATP and purinergic receptor activation play a critical role in determining the intracellular effects of key growth-regulating factors (11-13). Since hypoxic conditions favor proliferation and ATP release in endothelial cells (14, 15), we speculated that ATP release, if present in hyperoxia, could activate important survival pathways. Using primary HLMVEC, we demonstrate that ATP is released in hyperoxia and that the presence of extracellular ATP is essential for survival of these cells. We determined the effect of extracellular ATP on glucose uptake, PI3K activity, p70 S6 kinase phosphorylation, and ERK-1/2 phosphorylation in HLMVEC. Our findings strongly support the notion that extracellular ATP, through purinergic receptors, signals these important events.

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Vasodilatation of intrapulmonary arteries to P2‐receptor nucleotides in normal and pulmonary hypertensive newborn piglets

Cited by 26 publications

References 37 publications

ATP-induced vasodilation and purinergic receptors in the human leg: roles of nitric oxide, prostaglandins, and adenosine

ATP-induced vasodilation and purinergic receptors in the human leg: roles of nitric oxide, prostaglandins, and adenosine

Nitric Oxide–Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries

Extracellular ATP-mediated Signaling for Survival in Hyperoxia-induced Oxidative Stress

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