Mechanisms underlying selective coupling of endothelial Ca<sup>2+</sup> signals with eNOS <i>vs</i>. IK/SK channels in systemic and pulmonary arteries

Ottolini, Matteo; Daneva, Zdravka; Chen, Yen-Lin; Cope, Eric L.; Kasetti, Ramesh Babu; Zode, Gulab; Sonkusare, Swapnil K.

doi:10.1113/jp279570

Cited by 49 publications

(62 citation statements)

References 72 publications

(232 reference statements)

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“…In contrast, Ca 2+ influx conducted by endothelial TRPV4 is coupled to vasodilation. For example, Ca 2+ sparklets via endothelial TRPV4 activate eNOS to cause PA vasodilation [ 225 , 226 , 227 ]. Moreover, the PA vasodilator effect of a TRPV4 agonist is absent when NOS is inhibited [ 226 , 227 , 229 ], supporting the possibility that eNOS is downstream of TRPV4 in PAECs.…”

Section: Ros Modulation Of Augmented Pa Constrictionmentioning

confidence: 99%

“…For example, Ca 2+ sparklets via endothelial TRPV4 activate eNOS to cause PA vasodilation [ 225 , 226 , 227 ]. Moreover, the PA vasodilator effect of a TRPV4 agonist is absent when NOS is inhibited [ 226 , 227 , 229 ], supporting the possibility that eNOS is downstream of TRPV4 in PAECs. Another possible mechanism underlying TRPV4-mediated PA dilation is through small/intermediate conductance Ca 2+ -activated K + channels (SK Ca /IK Ca )-dependent endothelium-derived hyperpolarizing factor (EDHF) responses [ 226 ].…”

Section: Ros Modulation Of Augmented Pa Constrictionmentioning

confidence: 99%

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Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling

2020

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Elevated resistance of pulmonary circulation after chronic hypoxia exposure leads to pulmonary hypertension. Contributing to this pathological process is enhanced pulmonary vasoconstriction through both calcium-dependent and calcium sensitization mechanisms. Reactive oxygen species (ROS), as a result of increased enzymatic production and/or decreased scavenging, participate in augmentation of pulmonary arterial constriction by potentiating calcium influx as well as activation of myofilament sensitization, therefore mediating the development of pulmonary hypertension. Here, we review the effects of chronic hypoxia on sources of ROS within the pulmonary vasculature including NADPH oxidases, mitochondria, uncoupled endothelial nitric oxide synthase, xanthine oxidase, monoamine oxidases and dysfunctional superoxide dismutases. We also summarize the ROS-induced functional alterations of various Ca2+ and K+ channels involved in regulating Ca2+ influx, and of Rho kinase that is responsible for myofilament Ca2+ sensitivity. A variety of antioxidants have been shown to have beneficial therapeutic effects in animal models of pulmonary hypertension, supporting the role of ROS in the development of pulmonary hypertension. A better understanding of the mechanisms by which ROS enhance vasoconstriction will be useful in evaluating the efficacy of antioxidants for the treatment of pulmonary hypertension.

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Section: Ros Modulation Of Augmented Pa Constrictionmentioning

confidence: 99%

Section: Ros Modulation Of Augmented Pa Constrictionmentioning

confidence: 99%

Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling

2020

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“…Both ECs and SMCs control vascular contractility and arterial pressure. The expression of Panx1 and TRPV4 channels in both ECs and SMCs 8,18,[35][36][37] makes it challenging to decipher the cell type-specific roles of Panx1 and TRPV4 channels using global knockouts or pharmacological strategies. Therefore, studies utilizing EC-or SMC-specific knockout mice are necessary for a definitive assessment of the control of PAP by EC and SMC Panx1 and TRPV4 channels.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Pannexin 1–TRPV4 channel signaling lowers pulmonary arterial pressure

Daneva

Ottolini

Chen

et al. 2021

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Pannexin 1 (Panx1) is an ATP-efflux channel that controls endothelial function in the systemic circulation. However, the roles of endothelial Panx1 in resistance-sized pulmonary arteries (PAs) are unknown. Extracellular ATP dilates PAs through activation of endothelial TRPV4 (transient receptor potential vanilloid 4) ion channels. We hypothesized that endothelial Panx1–ATP–TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 or TRPV4 increased PA contractility and raised PAP. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase Cα (PKCα), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCα, and TRPV4 channels in PAs, promoting their spatial proximity and enabling signaling interactions. These results indicate that endothelial Panx1–P2Y2R–TRPV4 channel signaling, facilitated by caveolin-1, reduces PA contractility and lowers PAP.

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“…There is also heterogeneity in the mechanisms that give rise to specific functions. For example, the relative contributions of NO and endothelial-derived hyperpolarization to vasodilator responses differ in systemic and pulmonary circulations [75]. The contributions of these Ca 2+ -dependent dilator mechanisms differ also within specific vascular beds and depend on blood vessel calibre [76][77][78][79].…”

Section: Discussionmentioning

confidence: 99%

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

et al. 2020

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Background: Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations that give rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that endothelial cells are not a population of uniform cells but are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function. Purpose: To investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contribute to impaired vascular reactivity in obesity. Methods and results: To study obesity-related vascular function without complications associated with diabetes, a state of prediabetic obesity was induced in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and population-wide calcium responses. Obesity did not alter the slope of this relationship, but impaired calcium responses in the endothelial cell network. The network comprised structural and functional components. The structural architecture, a hexagonal lattice network of connected cells, was unchanged in obesity. The functional network contained sub-populations of clustered specialized agonist-sensing cells from which signals were communicated through the network. In obesity there were fewer but larger clusters of sensory cells and communication path lengths between clusters increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone. Conclusions: The distribution of cells in the endothelial network is critical in determining overall vascular response. Altered cell heterogeneity and arrangement in obesity decreases endothelial function and provides a novel framework for understanding compromised endothelial function in cardiovascular disease.

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Mechanisms underlying selective coupling of endothelial Ca²⁺ signals with eNOS vs. IK/SK channels in systemic and pulmonary arteries

Cited by 49 publications

References 72 publications

Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling

Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling

Endothelial Pannexin 1–TRPV4 channel signaling lowers pulmonary arterial pressure

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

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Mechanisms underlying selective coupling of endothelial Ca2+ signals with eNOS vs. IK/SK channels in systemic and pulmonary arteries

Cited by 49 publications

References 72 publications

Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling

Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling

Endothelial Pannexin 1–TRPV4 channel signaling lowers pulmonary arterial pressure

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

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Product

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Mechanisms underlying selective coupling of endothelial Ca²⁺ signals with eNOS vs. IK/SK channels in systemic and pulmonary arteries