Cytoskeletal Reorganization Evoked by Rho-associated kinase- and Protein Kinase C-catalyzed Phosphorylation of Cofilin and Heat Shock Protein 27, Respectively, Contributes to Myogenic Constriction of Rat Cerebral Arteries

Moreno‐Domínguez, Alejandro; El-Yazbi, Ahmed F.; Zhu, Hai‐Lei; Colinas, Olaia; Zhong, Xi; Walsh, Emma; Cole, Dylan M.; Kargacin, Gary J.; Walsh, Michael P.; Cole, William C.

doi:10.1074/jbc.m114.553743

Cited by 50 publications

(61 citation statements)

References 100 publications

(130 reference statements)

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“…Although our studies were performed in vessels from skeletal muscle, it has been demonstrated in rat middle cerebral arteries that 5-HT increases the phosphorylation state of cofilin and reduces the concentration of G-actin, indicating that 5-HT-induced remodeling of the actin cytoskeleton also occurs in the cerebral circulation (36), where localized vasoconstriction or vasospasm following subarachnoid hemorrhage or hemorrhagic stroke hinders blood flow re-establishment (8,12,39). Moreover, in a rat model of subarachnoid hemorrhage, inward remodeling of middle cerebral arteries, following exposure to hemolyzed blood, is blocked by inhibition of transglutaminases (17).…”

Section: ϫ4mentioning

confidence: 99%

Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization

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Castorena‐Gonzalez

Staiculescu

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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LA. Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization. Am J Physiol Heart Circ Physiol 310: H188 -H198, 2016. First published November 11, 2015; doi:10.1152/ajpheart.00666.2015.-Inward remodeling of the resistance vasculature is strongly associated with life-threatening cardiovascular events. Previous studies have demonstrated that both actin polymerization and the activation of transglutaminases mediate early stages of the transition from a structurally normal vessel to an inwardly remodeled one. Ex vivo studies further suggest that a few hours of exposure to vasoconstrictor agonists induces inward remodeling in the absence of changes in intraluminal pressure. Here we report that a short, 10-min, topical exposure to serotonin (5-HT) ϩ N -nitro-L-arginine methyl ester hydrochloride (L-NAME) was sufficient to initiate inward remodeling processes in rat cremasteric feed arterioles (100 -200 m lumen diameter), in vivo. Addition of the transglutaminase inhibitor, cystamine, blocked the in vivo remodeling. We further demonstrate that, in isolated arterioles, 5-HT ϩ L-NAME activates transglutaminases and modulates the phosphorylation state of cofilin, a regulator of actin depolymerization. The 5-HT ϩ L-NAME-induced remodeling process in isolated arterioles was also inhibited by an inhibitor of Lim Kinase, the kinase that phosphorylates and inactivates cofilin. Therefore, our results indicate that a brief vasoconstriction induced by 5-HT ϩ L-NAME is able to reduce the passive structural diameter of arterioles through processes that are dependent on the activation of transglutaminases and Lim kinase, and the subsequent phosphorylation of cofilin. inward remodeling; cytoskeleton; hypertension; vasospasm; vasoconstriction; nitric oxide NEW & NOTEWORTHYUsing intravital microscopy, we demonstrate that a brief exposure of the resistance vasculature to vasoconstrictors initiates inward remodeling processes, in vivo, via mechanism(s) that include the activation of transglutaminases and the reorganization of the actin cytoskeleton. This is the first study to examine the process in vivo, in real time.INWARD REMODELING OF THE RESISTANCE vasculature is a hallmark feature of a number of cardiovascular diseases including hypertension (31). The marked increase in the risk for lifethreatening cardiovascular events associated with inward remodeling (6, 34, 42) highlights its clinical importance. In addition, inward eutrophic remodeling of the resistance vasculature is believed to play an important role in increasing peripheral vascular resistance and decreasing tissue blood flow during the development and maintenance of essential hypertension (15). Inward remodeling is defined as a decrease in the luminal diameter of blood vessels under passive conditions (38). In essential hypertension, this remodeling is eutrophic; that is, there is no significant change in the cross-sectional area of the vascular wall, which indicates the...

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Section: ϫ4mentioning

confidence: 99%

Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization

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Castorena‐Gonzalez

Staiculescu

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…Of note, of 6 studies focusing especially on VSM, 5 reported increased cofilin phosphorylation in response to contractile stimulation. 39,[44][45][46][47] If one can conclude that vasodilation should lead to opposite changes, the majority of these studies are consistent with cofilin dephosphorylation being a relevant factor in controlling cytoskeletal changes, which ultimately lead to vasodilation. However, one vascular study also reported decreased phosphorylation with contraction.…”

Section: Discussionmentioning

confidence: 57%

“…Impaired actin polymerization indeed hampers contractile processes, despite unaltered MLC 20 phosphorylation levels. 38,39 Using confocal microscopy and differential ultracentrifugation, we were able to detect significant increases in the G-actin fraction after AMPK activation for 35 minutes. This effect of PT1 was indeed AMPK mediated because pretreatment with siRNA completely abolished the increase in G-actin.…”

Section: Discussionmentioning

confidence: 94%

“…39,[44][45][46][47] By contrast, in airway smooth muscle ADF (actin depolymerizing factor)/cofilin dephosphorylation was reported to occur during constriction, that is, a condition that goes along with actin polymerization. 48 We cannot explain the conflicting results at present, but differences between VSM and other tissues or the mode of preactivation of the muscle may play a role here.…”

Section: Discussionmentioning

confidence: 99%

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The AMP-Related Kinase (AMPK) Induces Ca ²⁺ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation

Schubert

Qiu

Blodow

et al. 2017

Circulation Research

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2+ sensitivity of vascular smooth muscle (VSM) allows for vasodilation without lowering of cytosolic Ca2+ . This may be particularly important in states requiring maintained dilation, such as hypoxia. AMP-related kinase (AMPK) is an important cellular energy sensor in VSM. Regulation of Ca 2+ sensitivity usually is attributed to myosin light chain phosphatase activity, but findings in non-VSM identified changes in the actin cytoskeleton. The potential role of AMPK in this setting is widely unknown.Objective: To assess the influence of AMPK on the actin cytoskeleton in VSM of resistance arteries with regard to potential Ca 2+ desensitization of VSM contractile apparatus. Methods and Results: AMPK induced a slowly developing dilation at unchanged cytosolic Ca2+ levels in potassium chloride-constricted intact arteries isolated from mouse mesenteric tissue. This dilation was not associated with changes in phosphorylation of myosin light chain or of myosin light chain phosphatase regulatory subunit. Using ultracentrifugation and confocal microscopy, we found that AMPK induced depolymerization of F-actin (filamentous actin). Imaging of arteries from LifeAct mice showed F-actin rarefaction in the midcellular portion of VSM. Immunoblotting revealed that this was associated with activation of the actin severing factor cofilin. Coimmunoprecipitation experiments indicated that AMPK leads to the liberation of cofilin from 14-3-3 protein.

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“…The nonmuscle actin cytoskeleton and FAs to which it is attached have been shown to display plasticity in the presence of agonists26 and biomechanical stimuli27, 28 by exhibiting stimulus‐induced increases in actin polymerization and endosomal‐dependent remodeling of a subset of FA proteins 29. Plasticity of the cortical cytoskeleton of VSMCs may contribute to the function of the healthy, compliant proximal aorta, acting as a tunable “shock absorber” that adapts in order to limit transmission of excessive pulsatile energy into the delicate downstream microvessels.…”

Section: Introductionmentioning

confidence: 99%

Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

Nicholson

Singh

Saphirstein

et al. 2018

JAHA

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BackgroundThe proximal aorta normally functions as a critical shock absorber that protects small downstream vessels from damage by pressure and flow pulsatility generated by the heart during systole. This shock absorber function is impaired with age because of aortic stiffening.Methods and ResultsWe examined the contribution of common genetic variation to aortic stiffness in humans by interrogating results from the AortaGen Consortium genome‐wide association study of carotid‐femoral pulse wave velocity. Common genetic variation in the N‐WASP (WASL) locus is associated with carotid‐femoral pulse wave velocity (rs600420, P=0.0051). Thus, we tested the hypothesis that decoy proteins designed to disrupt the interaction of cytoskeletal proteins such as N‐WASP with its binding partners in the vascular smooth muscle cytoskeleton could decrease ex vivo stiffness of aortas from a mouse model of aging. A synthetic decoy peptide construct of N‐WASP significantly reduced activated stiffness in ex vivo aortas of aged mice. Two other cytoskeletal constructs targeted to VASP and talin‐vinculin interfaces similarly decreased aging‐induced ex vivo active stiffness by on‐target specific actions. Furthermore, packaging these decoy peptides into microbubbles enables the peptides to be ultrasound‐targeted to the wall of the proximal aorta to attenuate ex vivo active stiffness.ConclusionsWe conclude that decoy peptides targeted to vascular smooth muscle cytoskeletal protein‐protein interfaces and microbubble packaged can decrease aortic stiffness ex vivo. Our results provide proof of concept at the ex vivo level that decoy peptides targeted to cytoskeletal protein‐protein interfaces may lead to substantive dynamic modulation of aortic stiffness.

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Cytoskeletal Reorganization Evoked by Rho-associated kinase- and Protein Kinase C-catalyzed Phosphorylation of Cofilin and Heat Shock Protein 27, Respectively, Contributes to Myogenic Constriction of Rat Cerebral Arteries

Cited by 50 publications

References 100 publications

Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization

Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization

The AMP-Related Kinase (AMPK) Induces Ca ²⁺ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation

Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

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Cytoskeletal Reorganization Evoked by Rho-associated kinase- and Protein Kinase C-catalyzed Phosphorylation of Cofilin and Heat Shock Protein 27, Respectively, Contributes to Myogenic Constriction of Rat Cerebral Arteries

Cited by 50 publications

References 100 publications

Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization

Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization

The AMP-Related Kinase (AMPK) Induces Ca 2+ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation

Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

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The AMP-Related Kinase (AMPK) Induces Ca ²⁺ -Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation