scholarly journals Smooth muscle Ca2+ sensitization causes hypercontractility of middle cerebral arteries in mice bearing the familial hemiplegic migraine type 2 associated mutation

2018 ◽  
Vol 39 (8) ◽  
pp. 1570-1587 ◽  
Author(s):  
Christian Staehr ◽  
Lise Hangaard ◽  
Elena V Bouzinova ◽  
Sukhan Kim ◽  
Rajkumar Rajanathan ◽  
...  
Keyword(s):  
Blood Flow ◽  
Vascular Function ◽  
Cerebral Arteries ◽  
Point Mutations ◽  
Familial Hemiplegic Migraine ◽  
Laser Speckle ◽  
Hemiplegic Migraine ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca

Familial hemiplegic migraine type 2 (FHM2) is associated with inherited point-mutations in the Na,K-ATPase α2 isoform, including G301R mutation. We hypothesized that this mutation affects specific aspects of vascular function, and thus compared cerebral and systemic arteries from heterozygote mice bearing the G301R mutation (Atp1a2+/−G301R) with wild type (WT). Middle cerebral (MCA) and mesenteric small artery (MSA) function was compared in an isometric myograph. Cerebral blood flow was assessed with Laser speckle analysis. Intracellular Ca2+ and membrane potential were measured simultaneously. Protein expression was semi-quantified by immunohistochemistry. Protein phosphorylation was analysed by Western blot. MSA from Atp1a2+/−G301R and WT showed similar contractile responses. The Atp1a2+/−G301R MCA constricted stronger to U46619, endothelin and potassium compared to WT. This was associated with an increased depolarization, although the Ca2+ change was smaller than in WT. The enhanced constriction of Atp1a2+/−G301R MCA was associated with increased cSrc activation, stronger sensitization to [Ca2+]i and increased MYPT1 phosphorylation. These differences were abolished by cSrc inhibition. Atp1a2+/−G301R mice had reduced resting blood flow through MCA in comparison with WT mice . FHM2-associated mutation leads to elevated contractility of MCA due to sensitization of the contractile machinery to Ca2+, which is mediated via Na,K-ATPase/Src-kinase/MYPT1 signalling.

scholarly journals Serial magnetic resonance imaging findings during severe attacks of familial hemiplegic migraine type 2: a case report

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
David Fear ◽  
Misha Patel ◽  
Ramin Zand
Keyword(s):  
Magnetic Resonance Imaging ◽  
Family History ◽  
Magnetic Resonance ◽  
Familial Hemiplegic Migraine ◽  
Imaging Findings ◽  
Resonance Imaging ◽  
Hemiplegic Migraine ◽  
Magnetic Resonance Imaging Mri ◽  
Mri Changes

Abstract Background Hemiplegic migraines represent a heterogeneous disorder with various presentations. Hemiplegic migraines are classified as sporadic or familial based on the presence of family history, but both subtypes have an underlying genetic etiology. Mutations in the ATP1A2 gene are responsible for Familial Hemiplegic type 2 (FHM2) or the sporadic hemiplegic migraine (SHM) counterpart if there is no family history of the disorder. Manifestations include migraine with aura and hemiparesis along with a variety of other symptoms likely dependent upon the specific mutation(s) present. Case presentation We report the case of an adult man who presented with headache, aphasia, and right-sided weakness. Workup for stroke and various infectious agents was unremarkable during the patient’s extended hospital stay. We emphasize the changes in the Magnetic Resonance Imaging (MRI) over time and the delay from onset of symptoms to MRI changes in Isotropic Diffusion Map (commonly referred to as Diffusion Weighted Imaging (DWI)) as well as Apparent Diffusion Coefficient (ADC). Conclusions We provide a brief review of imaging findings correlated with signs/symptoms and specific mutations in the ATP1A2 gene reported in the literature. Description of the various mutations and consequential presentations may assist neurologists in identifying cases of Hemiplegic Migraine, which may include transient changes in ADC and DWI imaging throughout the course of an attack.

scholarly journals Familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Fabio Antonaci ◽  
Sabrina Ravaglia ◽  
Gaetano S. Grieco ◽  
Stella Gagliardi ◽  
Cristina Cereda ◽  
...  
Keyword(s):  
Case Reports ◽  
3D Structure ◽  
Familial Hemiplegic Migraine ◽  
Transmembrane Helices ◽  
Hemiplegic Migraine ◽  
Case Presentation ◽  
Italian Family ◽  
Protein Prediction ◽  
Functional Consequences

Abstract Background The mechanisms of genotype-phenotype interaction in Familiar Hemiplegic migraine type 2 (FHM2) are still far from clear. Different ATP1A2 mutations have been described, with a spectrum of phenotypes ranging from mild to severe. No genotype-phenotype correlations have been attempted. Case presentation We describe an Italian family with FHM and a missense ATP1A2 variant (L425H) not previously described. The clinical picture was mild in all the affected members. Conclusions Co-segregation of the variant with the aura phenotype was complete in this family, suggesting a 100% penetrance. In silico protein prediction softwares indicate that this variant may change the 3D structure of ATPA1A2 at the cytoplasmic loop between the two central transmembrane helices. Milder FHM phenotypes are rarely reported in literature, likely because case reports are biased towards the most severe phenotypes, with milder forms possibly misdiagnosed as sporadic migraine with aura forms (MAs), even with complex auras. Further studies taking into account intra-familiar variability and functional consequences on the channel protein may help clarify genotype-phenotype correlations.

Early Treatment in Acute Severe Encephalopathy Caused by ATP1A2 Mutation of Familial Hemiplegic Migraine Type 2: Case Report and Literature Review

2019 ◽  
Vol 51 (03) ◽  
pp. 215-220
Author(s):  
Ying Du ◽  
Chuan Li ◽  
Feng-ju Duan ◽  
Chao Zhao ◽  
Wei Zhang
Keyword(s):  
Magnetic Resonance ◽  
Literature Review ◽  
Neuronal Damage ◽  
Brain Magnetic Resonance Imaging ◽  
Familial Hemiplegic Migraine ◽  
Resonance Spectroscopy ◽  
Rapid Progression ◽  
Complete Disappearance ◽  
Hemiplegic Migraine

AbstractFamilial hemiplegic migraine type 2 (FHM2) is an autosomal dominant inheritance disorder caused by ATP1A2 mutation, and the clinical spectrum is heterogeneous even with acute severe encephalopathy. However, up to now, early treatments against acute and severe attacks in FHM2 are still insufficient. Here, we report a 15-year-old female with intellectual disability due to FHM2 caused by a pathogenic ATP1A2 gene mutation, presenting mild-to-moderate headache at the onset, followed by confusion, complete right hemiparalysis, epileptic partial seizures, and conscious disturbance with rapid progression in acute attack. Brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy have revealed left extensive cerebral cortex edema, slightly decreased N-acetylaspartate for neuronal damage, and mildly increased lactate acid for mitochondrial dysfunction throughout the hemispheric swollen cortex. The patient is diagnosed as severe encephalopathy caused by FHM2. Based on literature review about pathophysiologic mechanism described in FHM2 recently, we use early treatments including prevention of glutamatergic excitotoxicity and protection of mitochondria function, as well as traditional antimigraine drug. The symptoms are all greatly improved and recovered within a short time, and follow-up MRI also shows complete disappearance of edema throughout the left hemispheric cortex. Altogether, the approach in our case may reduce the severity and duration of encephalopathy effectively, expend therapeutic options, and provide helpful references for acute severe encephalopathy in FHM2.

scholarly journals Activation of angiotensin type 2 receptor attenuates testosterone-induced hypertension and uterine vascular resistance in pregnant rats

2021 ◽  
Author(s):  
Jay S Mishra ◽  
Sathish Kumar
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Vascular Function ◽  
Uterine Artery ◽  
Artery Blood Flow ◽  
Protein Levels ◽  
Angiotensin Type 2 Receptor ◽  
Enos Protein ◽  
Angiotensin Type

Abstract Preeclampsia is a pregnancy-related hypertensive disorder with unclear mechanisms. While hypersensitivity to angiotensin II via vasoconstrictive angiotensin type-1 receptor (AT1R) is observed in preeclampsia, the importance of vasodilatory angiotensin type-2 receptor (AT2R) in the control of vascular dysfunction is less clear. We assessed whether AT1R, AT2R and eNOS expression is altered in placental vessels of preeclamptic women and tested if ex vivo incubation with AT2R agonist Compound 21 (C21; 1 μM) could restore AT1R, AT2R and eNOS balance. Further, using a rat model of gestational hypertension induced by elevated testosterone, we examined whether C21 (1 μg·kg−1·day−1, oral) could preserve AT1R and AT2R balance and improve blood pressure, uterine artery blood flow, and vascular function. Western blots revealed that AT1R protein level was higher while AT2R and eNOS protein were reduced in preeclamptic placental vessels, and AT2R agonist C21 decreased AT1R and increased AT2R and eNOS protein levels in preeclamptic vessels. In testosterone-dams, blood pressure was higher, and uterine artery blood flow was reduced, and C21 treatment reversed these levels similar to those in controls dams. C21 attenuated the exaggerated Ang II contraction and improved endothelium-dependent vasorelaxation in uterine arteries of testosterone-dams. These C21-mediated vascular effects were associated with decreased AT1R and increased AT2R and eNOS protein levels. C21 also increased serum nitrate/nitrite and bradykinin production in testosterone-dams and attenuated the feto-placental growth restriction. Thus, AT1R upregulation and AT2R downregulation is observed in preeclampsia and testosterone-model, and increasing AT2R activity could help restore AT1R and AT2R balance and improve gestational vascular function.

Haploinsufficiency of АТР1А2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2 (Nat. Genet. — 2003. — FEB. — 33(2). — P. 192—196: англ.)

2003 ◽  
Vol XXXV (1-2) ◽  
pp. 79-80
Author(s):  
M. De. Fusco ◽  
R. Marconi ◽  
L. Silvestri ◽  
L. Atorino ◽  
L. Rampoldi ◽  
...  
Keyword(s):  
Familial Hemiplegic Migraine ◽  
Entire Population ◽  
Hemiplegic Migraine ◽  
Western Countries

The prevalence of migraine in Western countries shows 12% of the entire population. One of the hereditary forms of the disease is familial hemiplegic migraine of the second type, which clinically manifests an aura, paroxysm of headache and the development of transient hemiparesis during an attack.

scholarly journals Effects of GV14 Acupuncture on Cerebral Blood Flow Velocity in the Basilar and Middle Cerebral Arteries and CO2 Reactivity during Hypercapnia in Normal Individuals

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Hyun Ku Lee ◽  
Sang-Kwan Moon ◽  
Chul Jin ◽  
Seung-Yeon Cho ◽  
Seong-Uk Park ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Flow Velocity ◽  
Blood Flow Velocity ◽  
Cerebral Arteries ◽  
Transcranial Doppler Sonography ◽  
Cerebrovascular Reactivity ◽  
Acupuncture Points ◽  
Co2 Reactivity ◽  
Middle Cerebral Arteries

The Governing Vessel 14 (GV14) (Dazhui) is one of the acupuncture points referred to as “seven acupoints for stroke.” Nevertheless, there is a scarcity of research on the effects of acupuncture treatment at GV14. This study investigated the effects of acupuncture at GV14 on cerebral blood flow (CBF), especially that in the basilar artery (BA) and the middle cerebral arteries (MCA). Sixteen healthy men aged 20 to 29 years were enrolled in this study. CBF velocity and cerebrovascular reactivity (CVR) were measured using transcranial Doppler sonography (TCD). The following were assessed: closed circuit rebreathing- (CCR-) induced carbon dioxide (CO2) reactivity, modified blood flow velocity at 40 mmHg (CV40) on BA and MCAs, blood pressure (BP), and heart rate (HR). Observed results were obtained after comparison with the baseline evaluation. Statistically significant elevations in CO2 reactivity were recorded in the BA (3.28 to 4.70, p < 0.001 ) and MCAs (right: 3.81 to 5.25, p = 0.001 ; left: 3.84 to 5.12, p = 0.005 ) after acupuncture at GV14. The CV40 increased statistically significantly only in the BA (45.49 to 50.41, p = 0.003 ). No change was observed in BP (106.83 to 107.08 (mmHg), p = 0.335 ) and HR (77 to 75 (bpm), p = 0.431 ). Acupuncture at GV14 improved CBF velocity. These results could be explained by the regulation of endothelium-dependent vessel dilation effected by acupuncture. This trial is registered with Korean Clinical Trial Registry (http://cris.nih.go.kr; registration number: KCT0004787).

Sex-specific differences in cerebral arterial myogenic tone in hypertensive and normotensive rats

2006 ◽  
Vol 290 (3) ◽  
pp. H1081-H1089 ◽  
Author(s):  
Jamila Ibrahim ◽  
Ann McGee ◽  
Delyth Graham ◽  
John C. McGrath ◽  
Anna F. Dominiczak
Keyword(s):  
Blood Flow ◽  
Cerebral Arteries ◽  
Systemic Blood Pressure ◽  
Limiting Factors ◽  
Myogenic Tone ◽  
Spontaneously Hypertensive ◽  
Cerebrovascular Events ◽  
Middle Cerebral Arteries ◽  
Wistar Kyoto ◽  
Strain Dependent

Cerebral blood flow (CBF) is maintained constant despite changes in systemic blood pressure (BP) through multiple mechanisms of autoregulation such as vascular myogenic reactivity. Our aim was to determine myogenic characteristics of cannulated middle cerebral arteries (MCA) in male and female stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) at 12 wk of age under pressurised no-flow conditions. MCA pressure-diameter relationships (20–200 mmHg) were constructed in active (with calcium) and passive (without calcium) conditions, and myogenic and mechanical properties were determined. Myogenic reactivity in WKY ( P < 0.05) and SHRSP ( P < 0.05) males was impaired compared with their female counterparts. Comparison of SHRSP with WKY in males revealed similar myogenic reactivity, but in females SHRSP exhibited augmented myogenic reactivity ( P < 0.05). In both sexes, myogenic tone yielded at lower pressure in SHRSP compared with WKY vessels (120–140 vs. 140–180 mmHg). Stress-strain relationships and elastic moduli in WKY rats showed that vessels were stiffer in females than in males. Conversely, in SHRSP, male vessels were stiffer than female vessels. Comparison of strains in males indicated that stiffness was increased in SHRSP compared with WKY vessels, whereas the converse was observed in females. These findings demonstrate that MCA myogenic and distensibility characteristics exhibit significant sex- and strain-dependent differences. Inappropriate myogenic adaptation and augmented vascular stiffness, particularly in male SHRSP, are potential limiting factors in blood flow autoregulation and may increase the predisposition for stroke-related cerebrovascular events.

Cerebral artery KATP- and KCa-channel activity and contractility: changes with development

2000 ◽  
Vol 279 (6) ◽  
pp. R2004-R2014 ◽  
Author(s):  
Wen Long ◽  
Lubo Zhang ◽  
Lawrence D. Longo
Keyword(s):  
Channel Blocker ◽  
Cerebral Arteries ◽  
Dependent Manner ◽  
Channel Activity ◽  
Channel Opener ◽  
Channel Inhibition ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca ◽  
Near Term ◽  
Nonpregnant Adult

The present study was designed to test the hypothesis that in cerebral arteries of the fetus, ATP-sensitive (KATP) and Ca2+-activated K+channels (KCa) play an important role in the regulation of intracellular Ca2+ concentration ([Ca2+]i) and that this differs significantly from that of the adult. In main branch middle cerebral arteries (MCA) from near-term fetal (∼140 days) and nonpregnant adult sheep, simultaneously we measured norepinephrine (NE)-induced responses of vascular tension and [Ca2+]i in the absence and presence of selective K+-channel openers/blockers. In fetal MCA, in a dose-dependent manner, both the KATP-channel opener pinacidil and the KCa-channel opener NS 1619 significantly inhibited NE-induced tension [negative logarithm of the half-maximal inhibitory concentration (pIC50) = 5.0 ± 0.1 and 8.2 ± 0.1, respectively], with a modest decrease of [Ca2+]i. In the adult MCA, in contrast, both pinacidil and NS 1619 produced a significant tension decrease (pIC50 = 5.1 ± 0.1 and 7.6 ± 0.1, respectively) with no change in [Ca2+]i. In addition, the KCa-channel blocker iberiotoxin (10−7 to 10−6 M) resulted in increased tension and [Ca2+]i in both adult and fetal MCA, although the KATP-channel blocker glibenclamide (10−7 to 3 × 10−5 M) failed to do so. Of interest, administration of 10−7 M iberiotoxin totally eliminated vascular contraction and increase in [Ca2+]i seen in response to 10−5M ryanodine. In precontracted fetal cerebral arteries, activation of the KATP and KCa channels significantly decreased both tension and [Ca2+]i, suggesting that both K+ channels play an important role in regulating L-type channel Ca2+ flux and therefore vascular tone in these vessels. In the adult, KATP and the KCa channels also appear to play an important role in this regard; however, in the adult vessel, activation of these channels with resultant vasorelaxation can occur with no significant change in [Ca2+]i. These channels show differing responses to inhibition, e.g., KCa-channel inhibition, resulting in increased tension and [Ca2+]i, whereas KATP-channel inhibition showed no such effect. In addition, the KCa channel appears to be coupled to the sarcoplasmic reticulum ryanodine receptor. Thus differences in plasma membrane K+-channel activity may account, in part, for the differences in the regulation of contractility of fetal and adult cerebral arteries.

A Chinese family with familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2

Cephalalgia ◽  
2019 ◽  
Vol 39 (11) ◽  
pp. 1382-1395
Author(s):  
Wenjing Tang ◽  
Meichen Zhang ◽  
Enchao Qiu ◽  
Shanshan Kong ◽  
Yingji Li ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Pathogenic Mutation ◽  
Familial Hemiplegic Migraine ◽  
Chinese Family ◽  
Hemiplegic Migraine ◽  
Pathogenic Potential ◽  
The Family

Background ATP1A2 has been identified as the genetic cause of familial hemiplegic migraine type 2. Over 80 ATP1A2 mutations have been reported, but no data from Chinese family studies has been included. Here, we report the first familial hemiplegic migraine type 2 Chinese family with a novel missense mutation. Methods Clinical manifestations in the family were recorded. Blood samples from patients and the unaffected members were collected for whole-exome sequencing to identify the pathogenic mutation. Seven online softwares (SIFT, PolyPhen-2, PROVEAN, PANTHER, MutationTaster2, MutationAssessor and PMut) were used for predicting the pathogenic potential of the mutation. PredictProtein, Jpred 4 and PyMOL were used to analyze structural changes of the protein. The mutation function was further tested by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Results All patients in the family had typical hemiplegic migraine attacks. Co-segregation of the mutation with the migraine phenotype in four generations, with 10 patients, was completed. The identified novel mutation, G762S in ATP1A2, exhibited the disease-causing feature by all the predictive softwares. The mutation impaired the local structure of the protein and decreased cell viability. Conclusion G762S in ATP1A2 is a novel pathogenic mutation identified in a Chinese family with familial hemiplegic migraine, which causes loss of function by changing the protein structure of the Na+/K+-ATPase α2 subunit.

PLA2 and TRPV4 channels regulate endothelial calcium in cerebral arteries

2007 ◽  
Vol 292 (3) ◽  
pp. H1390-H1397 ◽  
Author(s):  
Sean P. Marrelli ◽  
Roger G. O'Neil ◽  
Rachel C. Brown ◽  
Robert M. Bryan
Keyword(s):  
Transient Receptor Potential ◽  
Cerebral Arteries ◽  
Receptor Potential ◽  
Ruthenium Red ◽  
Transient Receptor Potential Vanilloid ◽  
Middle Cerebral Arteries ◽  
Trpv Channels ◽  
Intracellular Ca ◽  
Transient Receptor ◽  
Trpv4 Channel

We previously demonstrated that endothelium-derived hyperpolarizing factor (EDHF)-mediated dilations in cerebral arteries are significantly reduced by inhibitors of PLA2. In this study we examined possible mechanisms by which PLA2 regulates endothelium-dependent dilation, specifically whether PLA2 is involved in endothelial Ca2+ regulation through stimulation of TRPV4 channels. Studies were carried out with middle cerebral arteries (MCA) or freshly isolated MCA endothelial cells (EC) of male Long-Evans rats. Nitro-l-arginine methyl ester (l-NAME) and indomethacin were present throughout. In pressurized MCA, luminally delivered UTP produced increased EC intracellular Ca2+ concentration ([Ca2+]i) and MCA dilation. Incubation with PACOCF3, a PLA2 inhibitor, significantly reduced both EC [Ca2+]i and dilation responses to UTP. EC [Ca2+]i was also partially reduced by a transient receptor potential vanilloid (TRPV) channel blocker, ruthenium red. Manganese quenching experiments demonstrated Ca2+ influx across the luminal and abluminal face of the endothelium in response to UTP. Interestingly, PLA2-sensitive Ca2+ influx occurred primarily across the abluminal face. Luminal application of arachidonic acid, the primary product of PLA2 and a demonstrated activator of certain TRPV channels, increased both EC [Ca2+]i and MCA diameter. TRPV4 mRNA and protein was demonstrated in the endothelium by RT-PCR and immunofluorescence, respectively. Finally, application of 4α-phorbol 12,13-didecanoate (4αPDD), a TRPV4 channel activator, produced an increase in EC [Ca2+]i that was significantly reduced in the presence of ruthenium red. We conclude that PLA2 is involved in EC Ca2+ regulation through its regulation of TRPV4 channels. Furthermore, the PLA2-sensitive component of Ca2+ influx may be polarized to the abluminal face of the endothelium.

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