Regulation of vascular tone homeostasis by NO and H2S: Implications in hypertension

Gheibi, Sevda; Jeddi, Sajad; Kashfi, Khosrow; Ghasemi, Asghar

doi:10.1016/j.bcp.2018.01.017

Cited by 79 publications

(42 citation statements)

References 298 publications

(625 reference statements)

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“…Regulation of vascular tone involves a complex interplay of a variety of endogenous relaxant and constricting factors that are released under various physiological and pathophysiological circumstances from platelets, endothelial cells, and vascular smooth muscle (Gheibi, Jeddi, Kashfi, & Ghasemi, 2018;Jackson, 2018;Loh et al, 2018). The ENT4 substrates adenosine and 5-HT are prominent among these endogenous regulators.…”

Section: Discussionmentioning

confidence: 99%

Deletion of murine slc29a4 modifies vascular responses to adenosine and 5‐hydroxytryptamine in a sexually dimorphic manner

et al. 2020

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Equilibrative nucleoside transporter 4 (ENT4), encoded by SLC29A4, mediates the flux of both 5‐hydroxytryptamine (5‐HT) and adenosine across cell membranes. We hypothesized that loss of ENT4 function in mice would modify the effects of these established regulators of vascular function. Male and female wild‐type (WT) and slc29a4‐null (ENT4‐KO) mice were compared with respect to their hemodynamics and mesenteric vascular function. Male ENT4‐KO mice had a complete loss of myogenic tone in their mesenteric resistance arteries. This was accompanied by a decrease in blood flow in the superior mesenteric artery in the male ENT4‐KO mice, and a reduced responsiveness to 5‐HT. In contrast, endothelium‐dependent relaxations of mesenteric arteries from female ENT4‐KO mice were more sensitive to Ca2+‐activated K+ (KCa) channel blockade than WT mice. Female ENT4‐KO mice also demonstrated an enhanced vasodilatory response to adenosine in vivo that was not seen in males. Ketanserin (5‐HT2A inhibitor) and GR55562 (5‐HT1B/1D inhibitor) decreased 5‐HT‐induced tone, but only ketanserin inhibited the relaxant effect of 5‐HT in mesenteric arteries. 5‐HT‐evoked increases in tone were elevated in arteries from ENT4‐KO mice upon block of endothelial relaxant pathways, with arteries from female ENT4‐KO mice showing the greatest increase. Adenosine A2b receptor expression was decreased, while other adenosine transporter subtypes, as well as adenosine deaminase and adenosine kinase were increased in mesenteric arteries from male, but not female, ENT4‐KO mice. These findings indicate that deletion of slc29a4 leads to sex‐specific changes in vascular function with significant consequences for regulation of blood flow and pressure by adenosine and 5‐HT.

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Section: Discussionmentioning

confidence: 99%

Deletion of murine slc29a4 modifies vascular responses to adenosine and 5‐hydroxytryptamine in a sexually dimorphic manner

et al. 2020

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“…Like NO, H 2 S plays an important role in the vascular system with effects on BP, vasorelaxation and angiogenesis (Szabo, ; Gheibi et al ., ). Lower H 2 S production has been associated with myocardial ischaemia, angina and cardiovascular disease (Polhemus et al ., ).…”

Section: Dysregulation Of the Transsulfuration Pathways And Therapeutmentioning

confidence: 97%

Regulators of the transsulfuration pathway

Sbodio

Snyder

Paul

2018

British J Pharmacology

212

161

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The transsulfuration pathway is a metabolic pathway where transfer of sulfur from homocysteine to cysteine occurs. The pathway leads to the generation of several sulfur metabolites, which include cysteine, GSH and the gaseous signalling molecule hydrogen sulfide (H S). Precise control of this pathway is critical for maintenance of optimal cellular function and, therefore, the key enzymes of the pathway, cystathionine β-synthase and cystathionine γ-lyase, are regulated at multiple levels. Disruption of the transsulfuration pathway contributes to the pathology of several conditions such as vascular dysfunction, Huntington's disease and during ageing. Treatment with donors of hydrogen sulfide and/or stimulation of this pathway have proved beneficial in several of these disorders. In this review, we focus on the regulation of the transsulfuration pathway pertaining to cysteine and H S, which could be targeted to develop novel therapeutics.

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“…NO is a pivotal mediator of VEGF-induced responses and is essential for vascular function [ 29 ]. The regulation of NO production is very complex and it is noteworthy that both PPARγ and FABP4 are involved.…”

Section: Discussionmentioning

confidence: 99%

The Contribution of EDF1 to PPARγ Transcriptional Activation in VEGF-Treated Human Endothelial Cells

Cazzaniga

Locatelli

Castiglioni

et al. 2018

IJMS

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Vascular endothelial growth factor (VEGF) is important for maintaining healthy endothelium, which is crucial for vascular integrity. In this paper, we show that VEGF stimulates the nuclear translocation of endothelial differentiation-related factor 1 (EDF1), a highly conserved intracellular protein implicated in molecular events that are pivotal to endothelial function. In the nucleus, EDF1 serves as a transcriptional coactivator of peroxisome proliferator-activated receptor gamma (PPARγ), which has a protective role in the vasculature. Indeed, silencing EDF1 prevents VEGF induction of PPARγ activity as detected by gene reporter assay. Accordingly, silencing EDF1 markedly inhibits the stimulatory effect of VEGF on the expression of FABP4, a PPARγ-inducible gene. As nitric oxide is a marker of endothelial function, it is noteworthy that we report a link between EDF1 silencing, decreased levels of FABP4, and nitric oxide production. We conclude that EDF1 is required for VEGF-induced activation of the transcriptional activity of PPARγ.

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Regulation of vascular tone homeostasis by NO and H2S: Implications in hypertension

Cited by 79 publications

References 298 publications

Deletion of murine slc29a4 modifies vascular responses to adenosine and 5‐hydroxytryptamine in a sexually dimorphic manner

Deletion of murine slc29a4 modifies vascular responses to adenosine and 5‐hydroxytryptamine in a sexually dimorphic manner

Regulators of the transsulfuration pathway

The Contribution of EDF1 to PPARγ Transcriptional Activation in VEGF-Treated Human Endothelial Cells

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