Alterations of TMEM16a allostery in human retinal microarterioles in long‐standing hypertension

Gui, Dongmei; Li, Yanfeng; Chen, Xiaolong

doi:10.1002/iub.1376

Cited by 8 publications

(8 citation statements)

References 48 publications

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“…Recent inhibitors of TMEM16A, for example MONNA, CaCC(inh)‐A01 and T16A(inh)‐A01 , have been shown to suppress vascular constriction . However, our previous study demonstrated that these compounds relax rodent small mesenteric arteries even when the transmembrane Cl − gradient is abolished, suggesting a poor selectivity for TMEM16A .…”

mentioning

confidence: 74%

Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature

Jensen

Joergensen

Dam

et al. 2018

Basic Clin Pharma Tox

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TMEM16A is essential for Ca -activated Cl conductance in vascular smooth muscle. The importance of TMEM16A for agonist-induced vascular constriction and blood pressure control is, however, under debate. Previous studies suggested that TMEM16A might have a complex cellular function beyond being essential for the Ca -activated Cl conductance, for example modulation of Ca channel expression. Mice with constitutive, smooth muscle-specific expression of siRNA directed against Tmem16a (transgenic mice, TG) were generated. Isometric constrictions of isolated aorta, mesenteric, femoral and tail arteries from TG mice were compared with wild-types. Protein expression was analysed by Western blots. Blood pressure and heart rate were studied telemetrically. Significant TMEM16A down-regulation was seen in aorta and tail arteries, while no changes were detected in mesenteric and femoral arteries. Contractile responses of mesenteric and femoral arteries from TG and wild-type mice were not different. Aorta from TG mice showed reduced agonist-induced constriction, while their responses to elevated K were unchanged. Tail arteries from TG mice also constricted less to adrenergic stimulation than wild-types. Surprisingly, tail arteries from TG mice constricted less to elevated K too and were more sensitive to nifedipine-induced relaxation. Consistently, TMEM16A down-regulation in tail arteries was associated with reduction in CACNA1C protein (i.e. vascular L-type Ca channel) expression. No differences in blood pressure and heart rate between the groups were seen. This study suggests a complex contribution of TMEM16A in vascular function. We suggest that TMEM16A modulates arterial contractility, at least in part, indirectly via regulation of CACNA1C expression.

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mentioning

confidence: 74%

Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature

Jensen

Joergensen

Dam

et al. 2018

Basic Clin Pharma Tox

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“…Calmodulin has been found to be required for Ca 2+ ‐dependent regulation of endogenous CaCC activity in many native cells such as olfactory sensory neurons (Kaneko et al, ), pulmonary artery endothelial cells (Nilius et al, ), airway epithelial cells (Wagner et al, ), and lymphocytes (Nishimoto et al, ). Recently, Gui et al () reported that TMEM16A directly interacted with calmodulin in retina blood vessels obtained from human patients with chronic hypertension. In the heterologous expression system, direct interaction between calmodulin and TMEM16A has been demonstrated by several studies using immunoprecipitation and pull‐down assay (Tian et al, ; Jung et al, ; Vocke et al, ).…”

Section: Structural Determinants Of Tmem16amentioning

confidence: 99%

New Insights on the Regulation of Ca²⁺‐Activated Chloride Channel TMEM16A

Wang

et al. 2016

Journal Cellular Physiology

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TMEM16A, also known as anoctamin 1, is a recently identified Ca -activated chloride channel and the first member of a 10-member TMEM16 family. TMEM16A dysfunction is implicated in many diseases such as cancer, hypertension, and cystic fibrosis. TMEM16A channels are well known to be dually regulated by voltage and Ca . In addition, recent studies have revealed that TMEM16A channels are regulated by many molecules such as calmodulin, protons, cholesterol, and phosphoinositides, and a diverse range of stimuli such as thermal and mechanical stimuli. A better understanding of the regulatory mechanisms of TMEM16A is important to understand its physiological and pathological role. Recently, the crystal structure of a TMEM16 family member from the fungus Nectria haematococcaten (nhTMEM16) is discovered, and provides valuable information for studying the structure and function of TMEM16A. In this review, we discuss the structure and function of TMEM16A channels based on the crystal structure of nhTMEM16A and focus on the regulatory mechanisms of TMEM16A channels. J. Cell. Physiol. 232: 707-716, 2017. © 2016 Wiley Periodicals, Inc.

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“…35,83 However, hypertension-related downregulation of Ano1 has been always observed in the vasculature of the central nervous system, both in brain 63 and in the retina. 82 Thus, differences between previous reports may reflect modifications of Ano1 dynamics to adapt the vascular response to the specific needs of each tissue. Furthermore, studies in Ano1 knockout mice have demonstrated that the absence of this protein greatly reduces smooth muscle contraction.…”

Section: Discussionmentioning

confidence: 91%

“…18,64 The fine analysis of arteriolar annuli in KAP transgenic mice demonstrated that VICs are altered during hypertensive retinopathy, because there was a marked decrease in Ano1 expression and NADPH diaphorase activity in these cells. Previous reports concerning the status of Ano1 during hypertension are discordant, with some studies arguing for reduced Ano1 expression 63 or altered allostery, 82 whereas other studies reported increased Ano1 activity. 35,83 However, hypertension-related downregulation of Ano1 has been always observed in the vasculature of the central nervous system, both in brain 63 and in the retina.…”

Section: Discussionmentioning

confidence: 94%

Vascular Interstitial Cells in Retinal Arteriolar Annuli Are Altered During Hypertension

Ramos

Catita

López-Luppo

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. It has been suggested that arteriolar annuli localized in retinal arterioles regulate retinal blood flow acting as sphincters. Here, the morphology and protein expression profile of arteriolar annuli have been analyzed under physiologic conditions in the retina of wildtype, b-actin-Egfp, and Nestin-gfp transgenic mice. Additionally, to study the effect of hypertension, the KAP transgenic mouse has been used. METHODS. Cellular architecture has been studied using digested whole mount retinas and transmission electron microscopy. The profile of protein expression has been analyzed on paraffin sections and whole mount retinas by immunofluorescence and histochemistry. RESULTS. The ultrastructural analysis of arteriolar annuli showed a different cell population found between endothelial and muscle cells that matched most of the morphologic criteria established to define interstitial Cajal cells. The profile of protein expression of these vascular interstitial cells (VICs) was similar to that of interstitial Cajal cells and different from the endothelial and smooth muscle cells, because they expressed b-actin, nestin, and CD44, but they did not express CD31 and a-SMA or scarcely express F-actin. Furthermore, VICs share with pericytes the expression of NG2 and platelet-derived growth factor receptor beta (PDGFR-b). The high expression of Ano1 and high activity of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase observed in VICs was diminished during hypertensive retinopathy suggesting that these cells might play a role on the motility of arteriolar annuli and that this function is altered during hypertension. CONCLUSIONS. A novel type of VICs has been described in the arteriolar annuli of mouse retina. Remarkably, these cells undergo important molecular modifications during hypertensive retinopathy and might thus be a therapeutic target against this disease.

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Alterations of TMEM16a allostery in human retinal microarterioles in long‐standing hypertension

Cited by 8 publications

References 48 publications

Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature

Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature

New Insights on the Regulation of Ca²⁺‐Activated Chloride Channel TMEM16A

Vascular Interstitial Cells in Retinal Arteriolar Annuli Are Altered During Hypertension

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Alterations of TMEM16a allostery in human retinal microarterioles in long‐standing hypertension

Cited by 8 publications

References 48 publications

Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature

Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature

New Insights on the Regulation of Ca2+‐Activated Chloride Channel TMEM16A

Vascular Interstitial Cells in Retinal Arteriolar Annuli Are Altered During Hypertension

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New Insights on the Regulation of Ca²⁺‐Activated Chloride Channel TMEM16A