Ion Channels in Endothelial Responses to Fluid Shear Stress

Gerhold, Kristin A.; Schwartz, Martin A.

doi:10.1152/physiol.00007.2016

Cited by 62 publications

(48 citation statements)

References 131 publications

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“…A hallmark of endothelial dysfunction is a reduction in NO production in response to increased flow; however, the mechanisms governing the development of endothelial dysfunction under hypercholesterolemic conditions are unclear. We previously showed that hypercholesterolemia suppresses endothelial Kir channels, putative mechanosensors . We recently identified endothelial Kir2.1 channels as a critical component of FIV whereby activation of Kir2.1 promotes Akt phosphorylation and ultimately results in NO production and vasodilation in resistance arteries .…”

Section: Discussionmentioning

confidence: 99%

“…We previously showed that hypercholesterolemia suppresses endothelial Kir channels, 15,26 putative mechanosensors. 37,38 We recently identified endothelial Kir2.1 channels as a critical component of FIV whereby activation of Kir2.1 promotes Akt phosphorylation and ultimately results in NO production and vasodilation in resistance arteries. 3 In the current study, we show for the first time that suppression of Kir channels is a key contributor to endothelial dysfunction in Apoe À/À mice, a major mouse model of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

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Hypercholesterolemia‐Induced Loss of Flow‐Induced Vasodilation and Lesion Formation in Apolipoprotein E–Deficient Mice Critically Depend on Inwardly Rectifying K ⁺ Channels

Fancher

Ahn

Adamos

et al. 2018

JAHA

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BackgroundHypercholesterolemia‐induced decreased availability of nitric oxide (NO) is a major factor in cardiovascular disease. We previously established that cholesterol suppresses endothelial inwardly rectifying K+ (Kir) channels and that Kir2.1 is an upstream mediator of flow‐induced NO production. Therefore, we tested the hypothesis that suppression of Kir2.1 is responsible for hypercholesterolemia‐induced inhibition of flow‐induced NO production and flow‐induced vasodilation (FIV). We also tested the role of Kir2.1 in the development of atherosclerotic lesions.Methods and ResultsKir2.1 currents are significantly suppressed in microvascular endothelial cells exposed to acetylated–low‐density lipoprotein or isolated from apolipoprotein E–deficient (Apoe −/−) mice and rescued by cholesterol depletion. Genetic deficiency of Kir2.1 on the background of hypercholesterolemic Apoe −/−mice, Kir2.1 +/− /Apoe −/− exhibit the same blunted FIV and flow‐induced NO response as Apoe −/−or Kir2.1 +/− alone, but while FIV in Apoe −/− mice can be rescued by cholesterol depletion, in Kir2.1 +/− /Apoe −/− mice cholesterol depletion has no effect on FIV. Endothelial‐specific overexpression of Kir2.1 in arteries from Apoe −/− and Kir2.1 +/− /Apoe −/− mice results in full rescue of FIV and NO production in Apoe −/− mice with and without the addition of a high‐fat diet. Conversely, endothelial‐specific expression of dominant‐negative Kir2.1 results in the opposite effect. Kir2.1 +/− /Apoe −/−mice also show increased lesion formation, particularly in the atheroresistant area of descending aorta.ConclusionsWe conclude that hypercholesterolemia‐induced reduction in FIV is largely attributable to cholesterol suppression of Kir2.1 function via the loss of flow‐induced NO production, whereas the stages downstream of flow‐induced Kir2.1 activation appear to be mostly intact. Kir2.1 channels also have an atheroprotective role.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia‐Induced Loss of Flow‐Induced Vasodilation and Lesion Formation in Apolipoprotein E–Deficient Mice Critically Depend on Inwardly Rectifying K ⁺ Channels

Fancher

Ahn

Adamos

et al. 2018

JAHA

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“…This study (6) provided a key link between in vivo pathophysiology and in vitro modeling that strengthens the rationale for the current systems biology approach.There are several well-defined mechanisms for endothelial responses to different shears. ECs feature several mechanosensors that include vascular endothelial (VE)-cadherin, integrins, and ion channels (7,8). The up-regulation of Krüppel-like factor 2 (KLF2) is a well-established hallmark of endothelial response to laminar flow (and PS) (9, 10), along with endothelial nitric oxide synthase (eNOS) up-regulation and activity (11).…”

mentioning

confidence: 99%

Systems biology analysis of longitudinal functional response of endothelial cells to shear stress

Ajami

Gupta

Maurya

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

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Blood flow and vascular shear stress patterns play a significant role in inducing and modulating physiological responses of endothelial cells (ECs). Pulsatile shear (PS) is associated with an atheroprotective endothelial phenotype, while oscillatory shear (OS) is associated with an atheroprone endothelial phenotype. Although mechanisms of endothelial shear response have been extensively studied, most studies focus on characterization of single molecular pathways, mainly at fixed time points after stress application. Here, we carried out a longitudinal time-series study to measure the transcriptome after the application of PS and OS. We performed systems analyses of transcriptional data of cultured human vascular ECs to elucidate the dynamics of endothelial responses in several functional pathways such as cell cycle, oxidative stress, and inflammation. By combining the temporal data on differentially expressed transcription factors and their targets with existing knowledge on relevant functional pathways, we infer the causal relationships between disparate endothelial functions through common transcriptional regulation mechanisms. Our study presents a comprehensive temporally longitudinal experimental study and mechanistic model of shear stress response. By comparing the relative endothelial expressions of genes between OS and PS, we provide insights and an integrated perspective into EC function in response to differential shear. This study has significant implications for the pathogenesis of vascular diseases.

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“…PORH is thought to be mainly mediated by shear stress associated with the rapid increase in blood flow. In vitro studies have demonstrated that endothelial K Ca and K ATP channels are shear stress sensitive, and thus, a rapid increase in cutaneous blood flow following arterial occlusion may activate these K + channels in the endothelial cell, causing hyperpolarization and thus vasodilatation. Furthermore, arterial occlusion causes local hypoxia, which can cause vasodilatation in human skin .…”

Section: Discussionmentioning

confidence: 99%

Tetraethylammonium, glibenclamide, and 4‐aminopyridine modulate post‐occlusive reactive hyperemia in non‐glabrous human skin with no roles of NOS and COX

et al. 2019

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Objectives Post‐occlusive reactive hyperemia (PORH) following arterial occlusion is widely used to assess cutaneous microvascular function, though the underlying mechanisms remain to be fully elucidated. We evaluated the hypothesis that Ca2+‐activated, ATP‐sensitive, and voltage‐gated K+ channels (KCa, KATP, and KV channels, respectively) contribute to PORH while nitric oxide synthase (NOS) and cyclooxygenase (COX) do not. Methods On separate occasions, cutaneous blood flow (laser Doppler flowmetry) was monitored before and following 5‐min arterial occlusion at forearm skin sites treated via microdialysis with the following: Experiment 1 (n = 11): (a) lactated Ringer solution (Control), (b) 10 mM Nω‐nitro‐L‐arginine (NOS inhibitor), (c) 10 mM ketorolac (COX inhibitor), and (d) combined NOS+COX inhibition; Experiment 2 (n = 14): (a) lactated Ringer solution (Control), (b) 50 mM tetraethylammonium (non‐selective KCa channel blocker), (c) 5 mM glibenclamide (non‐specific KATP channel blocker), and (d) 10 mM 4‐aminopyridine (non‐selective KV channel blocker). Results Separate and combined NOS and COX inhibition did not influence PORH. Conversely, tetraethylammonium and glibenclamide attenuated, whereas 4‐aminopyridine augmented PORH. Conclusions We showed that tetraethylammonium, glibenclamide, and 4‐aminopyridine modulate PORH with no roles of NOS and COX in human non‐glabrous forearm skin in vivo. Thus, cutaneous PORH changes could reflect altered K+ channel function.

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Ion Channels in Endothelial Responses to Fluid Shear Stress

Cited by 62 publications

References 131 publications

Hypercholesterolemia‐Induced Loss of Flow‐Induced Vasodilation and Lesion Formation in Apolipoprotein E–Deficient Mice Critically Depend on Inwardly Rectifying K ⁺ Channels

Hypercholesterolemia‐Induced Loss of Flow‐Induced Vasodilation and Lesion Formation in Apolipoprotein E–Deficient Mice Critically Depend on Inwardly Rectifying K ⁺ Channels

Systems biology analysis of longitudinal functional response of endothelial cells to shear stress

Tetraethylammonium, glibenclamide, and 4‐aminopyridine modulate post‐occlusive reactive hyperemia in non‐glabrous human skin with no roles of NOS and COX

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Ion Channels in Endothelial Responses to Fluid Shear Stress

Cited by 62 publications

References 131 publications

Hypercholesterolemia‐Induced Loss of Flow‐Induced Vasodilation and Lesion Formation in Apolipoprotein E–Deficient Mice Critically Depend on Inwardly Rectifying K + Channels

Hypercholesterolemia‐Induced Loss of Flow‐Induced Vasodilation and Lesion Formation in Apolipoprotein E–Deficient Mice Critically Depend on Inwardly Rectifying K + Channels

Systems biology analysis of longitudinal functional response of endothelial cells to shear stress

Tetraethylammonium, glibenclamide, and 4‐aminopyridine modulate post‐occlusive reactive hyperemia in non‐glabrous human skin with no roles of NOS and COX

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Hypercholesterolemia‐Induced Loss of Flow‐Induced Vasodilation and Lesion Formation in Apolipoprotein E–Deficient Mice Critically Depend on Inwardly Rectifying K ⁺ Channels

Hypercholesterolemia‐Induced Loss of Flow‐Induced Vasodilation and Lesion Formation in Apolipoprotein E–Deficient Mice Critically Depend on Inwardly Rectifying K ⁺ Channels