Intravascular flow stimulates PKD2 (polycystin-2) channels in endothelial cells to reduce blood pressure

Mackay, Charles; Leo, M. Dennis; Fernández‐Peña, Carlos; Hasan, Raquibul; Yin, Weiqiang; Mata-Daboin, Alejandro; Bulley, Simon; Gammons, Jesse; Mancarella, Salvatore; Jaggar, Jonathan H.

doi:10.7554/elife.56655

Cited by 34 publications

(71 citation statements)

References 66 publications

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“…Peripheral endothelial cells and BECs express receptors to respond to several extracellular stimuli like chemical transmitters, stretching, mechanical force, temperature, osmotic pressure and pH changes, most of them coupled to G‐protein coupled receptors that activate second messenger pathways that involve [Ca 2+ ] i mobilization from internal stores 9,10,14,35 . We found that shifting the perfusion line to apply different drugs to BECs produced a transient [Ca 2+ ] i response, which could be generated by the expression of mechanical‐activated receptors coupled to [Ca 2+ ] i dynamics 35 . For instance, TRPV5 and TRPV6 channels are constitutively open, are highly permeable to Ca 2+ and are widely expressed in the brain, 36 although their expression has not been yet demonstrated in BECs.…”

Section: Discussionmentioning

confidence: 88%

Angiotensin II, ATP and high extracellular potassium induced intracellular calcium responses in primary rat brain endothelial cell cultures

García‐Carlos

Camargo‐Loaiza

García-Villa

et al. 2021

Cell Biochemistry & Function

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The meninges shield the nervous system from diverse, rather harmful stimuli and pathogens from the periphery. This tissue is composed of brain endothelial cells (BECs) that express diverse ion channels and chemical‐transmitter receptors also expressed by neurons and glial cells to communicate with each other. However, information about the effects of ATP and angiotensin II on BECs is scarce, despite their essential roles in blood physiology. This work investigated in vitro if BECs from the meninges from rat forebrain respond to ATP, angiotensin II and high extracellular potassium, with intracellular calcium mobilizations and its second messenger‐associated pathways. We found that in primary BEC cultures, both ATP and angiotensin II produced intracellular calcium responses linked to the activation of inositol trisphosphate receptors and ryanodine receptors, which led to calcium release from intracellular stores. We also used RT‐PCR to explore what potassium channel subunits are expressed by primary BEC cultures and freshly isolated meningeal tissue, and which might be linked to the observed effects. We found that BECs mainly expressed the inward rectifier potassium channel subunits Kir1.1, Kir3.3, Kir 4.1 and Kir6.2. This study contributes to the understanding of the functions elicited by ATP and angiotensin II in BECs from rat meninges. SIGNIFICANCE OF THE STUDY Brain endothelial cells (BECs) express diverse ion channels and membrane receptors, which they might use to communicate with neurons and glia. This work investigated in vitro, if BECs from the rat forebrain respond to angiotensin II and ATP with intracellular calcium mobilizations. We found that these cells did respond to said substances with intracellular calcium mobilizations linked to inositol trisphosphate and ryanodine receptor activation, which led to calcium release from intracellular stores. These findings are important because they might uncover routes of active communication between brain cells and endothelial cells.

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Section: Discussionmentioning

confidence: 88%

Angiotensin II, ATP and high extracellular potassium induced intracellular calcium responses in primary rat brain endothelial cell cultures

García‐Carlos

Camargo‐Loaiza

García-Villa

et al. 2021

Cell Biochemistry & Function

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“…In this regard, TRPA1 and TRPV3 channels have been shown to be important Ca 2+ influx pathways in arterial endothelium from other vascular beds [34, 38]. Moreover, TRPP1 channels were recently proposed as an endothelial Ca 2+ influx pathway that mediates flow-induced vasodilation [39]. Whether TRPA1/TRPV3/TRPP1 channels are functional in venous endothelium has not been investigated.…”

Section: Discussion/conclusionmentioning

confidence: 99%

Calcium Signal Profiles in Vascular Endothelium from Cdh5-GCaMP8 and Cx40-GCaMP2 Mice

et al. 2021

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Introduction: Studies in Cx40-GCaMP2 mice, which express calcium biosensor GCaMP2 in the endothelium under connexin 40 promoter, have identified the unique properties of endothelial calcium signals. However, Cx40-GCaMP2 mouse is associated with a narrow dynamic range and lack of signal in the venous endothelium. Recent studies have proposed many GCaMPs (GCaMP5/6/7/8) with improved properties although their performance in endothelium-specific calcium studies is not known. Methods: We characterized a newly developed mouse line that constitutively expresses GCaMP8 in the endothelium under the VE-cadherin (Cdh5-GCaMP8) promoter. Calcium signals through endothelial IP3 receptors and TRP vanilloid 4 (TRPV4) ion channels were recorded in mesenteric arteries (MAs) and veins from Cdh5-GCaMP8 and Cx40-GCaMP2 mice. Results: Cdh5-GCaMP8 mice showed lower baseline fluorescence intensity, higher dynamic range, and higher amplitudes of individual calcium signals than Cx40-GCaMP2 mice. Importantly, Cdh5-GCaMP8 mice enabled the first recordings of discrete calcium signals in the intact venous endothelium and revealed striking differences in IP3 receptor and TRPV4 channel calcium signals between MAs and mesenteric veins. Conclusion: Our findings suggest that Cdh5-GCaMP8 mice represent significant improvements in dynamic range, sensitivity for low-intensity signals, and the ability to record calcium signals in venous endothelium.

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“…2 Notably, polycystin 1 and 2 are expressed in vascular endothelial and vascular smooth muscle cells. 3,4 Primary cilia defects that characterize ADPKD are associated with dysfunction in endothelial cilia, affecting calcium and nitric oxide signaling that can consequentially lead to vascular disorders such as hypertension. 5 Hypertension occurs in greater than 60% of individuals with ADPKD before the loss of kidney function, resulting in a much earlier diagnosis of hypertension than the general population and is closely associated with TKV.…”

Section: Introductionmentioning

confidence: 99%

PKD1 Compared With PKD2 Genotype and Cardiac Hospitalizations in the Halt Progression of Polycystic Kidney Disease Studies

Steele

You

Gitomer

et al. 2022

Kidney International Reports

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

Intravascular flow stimulates PKD2 (polycystin-2) channels in endothelial cells to reduce blood pressure

Cited by 34 publications

References 66 publications

Angiotensin II, ATP and high extracellular potassium induced intracellular calcium responses in primary rat brain endothelial cell cultures

Angiotensin II, ATP and high extracellular potassium induced intracellular calcium responses in primary rat brain endothelial cell cultures

Calcium Signal Profiles in Vascular Endothelium from Cdh5-GCaMP8 and Cx40-GCaMP2 Mice

PKD1 Compared With PKD2 Genotype and Cardiac Hospitalizations in the Halt Progression of Polycystic Kidney Disease Studies

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