Intravascular pressure augments cerebral arterial constriction by inducing voltage-insensitive Ca<sup>2+</sup>waves

Mufti, Rania E.; Brett, Suzanne E.; Tran, Cam Ha T.; El-Rahman, Rasha Abd; Anfinogenova, Yana; El-Yazbi, Ahmed F.; Cole, William C.; Jones, Peter P.; Chen, S.R. Wayne; Welsh, Donald G.

doi:10.1113/jphysiol.2010.193300

Cited by 59 publications

(77 citation statements)

References 72 publications

(197 reference statements)

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“…The latter observation aligns with previous myogenic experiments using ryanodine. 10 Together, these observations indirectly suggest that α v β 3 integrins contribute to SR store mobilization and Ca 2+ wave generation, independent of L-type Ca 2+ channel activity. The preceding analysis assumes that RGD peptides have few nonmyogenic effects.…”

Section: Waves and Mlc 20 Phosphorylationmentioning

confidence: 88%

Implications of α _v β ₃ Integrin Signaling in the Regulation of Ca ²⁺ Waves and Myogenic Tone in Cerebral Arteries

Mufti

Zechariah

Sancho

et al. 2015

ATVB

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Objective-The myogenic response is central to blood flow regulation in the brain. Its induction is tied to elevated cytosolic [Ca 2+ ], a response primarily driven by voltage-gated Ca 2+ channels and secondarily by Ca 2+ wave production. Although the signaling events leading to the former are well studied, those driving Ca 2+ waves remain uncertain. Approach and Results-We postulated that α v β 3 integrin signaling is integral to the generation of pressure-induced Ca 2+ waves and cerebral arterial tone. This hypothesis was tested in rat cerebral arteries using the synergistic strengths of pressure myography, rapid Ca 2+ imaging, and Western blot analysis. GRGDSP, a peptide that preferentially blocks α v β 3 integrin, attenuated myogenic tone, indicating the modest role for sarcoplasmic reticulum Ca 2+ release in myogenic tone generation. The RGD peptide was subsequently shown to impair Ca 2+ wave generation and myosin light chain 20 (MLC 20 ) phosphorylation, the latter of which was attributed to the modulation of MLC kinase and MLC phosphatase via MYPT1-T855 phosphorylation. Subsequent experiments revealed that elevated pressure enhanced phospholipase Cγ1 phosphorylation in an RGD-dependent manner and that phospholipase C inhibition attenuated Ca 2+ wave generation. Direct inhibition of inositol 1, 4, 5-triphosphate receptors also impaired Ca 2+ wave generation, myogenic tone, and MLC 20 phosphorylation, partly through the T-855 phosphorylation site of MYPT1. Conclusions-Our investigation reveals a hitherto unknown role for α v β 3 integrin as a cerebral arterial pressure sensor.The membrane receptor facilitates Ca 2+ wave generation through a signaling cascade, involving phospholipase Cγ1, inositol 1,3,4 triphosphate production, and inositol 1, 4, 5-triphosphate receptor activation. These discrete asynchronous Ca 2+ events facilitate MLC 20 phosphorylation and, in part, myogenic tone by influencing both MLC kinase and MLC phosphatase activity. 18,20,21 In this study of the cerebral circulation, we investigated whether the α V β 3 integrin facilitates Ca 2+ wave generation and myogenic tone through a signaling cascade, involving PLCγ1 and IP 3 R. To test this hypothesis, we used a methodological approach that synergistically combined pressure myography, rapid Ca 2+ imaging, and Western blot analysis. We found that inhibiting α V β 3 integrin partially impaired myogenic tone, demonstrating the modest role of SR Ca 2+ waves in the generation of myogenic tone. Consistent with the functional observations, elevated pressure was also shown to increase Ca 2+ wave generation in rat cerebral arteries. These pressureinduced Ca 2+ events were attenuated by α V β 3 -blocking peptides and facilitated MLC 20 phosphorylation by augmenting MLCK activity and inhibiting MLCP via the phosphorylation of MYPT1-T855. Further experiments revealed that: (1) elevated pressure augmented PLCγ1 phosphorylation in a α V β 3 -dependent manner and (2) inhibiting PLC or IP 3 Rs diminished myogenic tone, Ca 2+ wave production, and MLC ...

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Section: Waves and Mlc 20 Phosphorylationmentioning

confidence: 88%

Implications of α _v β ₃ Integrin Signaling in the Regulation of Ca ²⁺ Waves and Myogenic Tone in Cerebral Arteries

Mufti

Zechariah

Sancho

et al. 2015

ATVB

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“…Ca 2 þ channel blockers and removal of extracellular Ca 2 þ are well known to abolish the myogenic response. 43,48 This does not mean, however, that MLCP inhibition and actin polymerization are not involved in the myogenic response since cross-bridge cycling absolutely requires LC 20 phosphorylation, which generally requires an increase in [Ca 2 þ ] i . It is important to note, therefore, that any treatment or manipulation that directly or indirectly affects the activity of voltage-gated Ca 2 þ channels or Ca 2 þ influx may confound interpretation of the involvement of MLCP inhibition and dynamic regulation of the actin cytoskeleton.…”

Section: Discussionmentioning

confidence: 99%

“…41 It was initially considered that the myogenic response is due exclusively to increased MLCK activity. 6 However, pressure elevation also evokes asynchronous Ca 2 þ waves within individual vascular smooth muscle cells because of release of Ca 2 þ from the sarcoplasmic reticulum, 42,43 similarly to the Ca 2 þ waves observed during agonist-induced contraction. 44 Thus, myogenic constriction is suppressed by membrane hyperpolarization, block of voltagegated Ca 2 þ channels, removal of extracellular Ca 2 þ , or application of ML-7 (which inhibits MLCK activity).…”

Section: The Mechanosensormentioning

confidence: 99%

“…44 Thus, myogenic constriction is suppressed by membrane hyperpolarization, block of voltagegated Ca 2 þ channels, removal of extracellular Ca 2 þ , or application of ML-7 (which inhibits MLCK activity). 2,6,43,45,46 The extent of myogenic depolarization must be precisely controlled to obtain an appropriate increase in [ 6,42 However, these changes are not sufficient to explain the phenomenon. 2,7,11,[53][54][55][56] On the basis of the three phases described in Figure 1 Figure 3) and was first described for agonist-induced smooth muscle contraction.…”

Section: The Mechanosensormentioning

confidence: 99%

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The Role of Actin Filament Dynamics in the Myogenic Response of Cerebral Resistance Arteries

Walsh

Cole

2012

J Cereb Blood Flow Metab

103

107

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The myogenic response has a critical role in regulation of blood flow to the brain. Increased intraluminal pressure elicits vasoconstriction, whereas decreased intraluminal pressure induces vasodilatation, thereby maintaining flow constant over the normal physiologic blood pressure range. Improved understanding of the molecular mechanisms underlying the myogenic response is crucial to identify deficiencies with pathologic consequences, such as cerebral vasospasm, hypertension, and stroke, and to identify potential therapeutic targets. Three mechanisms have been suggested to be involved in the myogenic response: (1) membrane depolarization, which induces Ca 2 þ entry, activation of myosin light chain kinase, phosphorylation of the myosin regulatory light chains (LC 20 ), increased actomyosin MgATPase activity, cross-bridge cycling, and vasoconstriction; (2) activation of the RhoA/Rho-associated kinase (ROCK) pathway, leading to inhibition of myosin light chain phosphatase by phosphorylation of MYPT1, the myosin targeting regulatory subunit of the phosphatase, and increased LC 20 phosphorylation; and (3) activation of the ROCK and protein kinase C pathways, leading to actin polymerization and the formation of enhanced connections between the actin cytoskeleton, plasma membrane, and extracellular matrix to augment force transmission. This review describes these three mechanisms, emphasizing recent developments regarding the importance of dynamic actin polymerization in the myogenic response of the cerebral vasculature.

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“…The role of Ca 2þ waves in vascular SM is not fully understood, although waves in pial arteries may contribute to myogenic tone development, particularly at lower pressures. 63 In contrast, Ca 2þ sparks are highly localized, brief events activates G q -coupled P2Y receptors on the SM, leading to PLC activation. Through an as-yet-undefined pathway in parenchymal arterioles (see text for insights from pial arteries 21 ), PLC activation leads to a depolarizing Na þ influx through TRPM4, triggering Ca 2þ influx through VDCCs and leading to myocyte contraction.…”

Section: Ryanodine Receptors In Smooth Muscle: Ca 2þ -Release Channelmentioning

confidence: 99%

Ion channel networks in the control of cerebral blood flow

Longden

Hill-Eubanks

Nelson

2015

J Cereb Blood Flow Metab

119

115

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One hundred and twenty five years ago, Roy and Sherrington made the seminal observation that neuronal stimulation evokes an increase in cerebral blood flow.1 Since this discovery, researchers have attempted to uncover how the cells of the neurovascular unit-neurons, astrocytes, vascular smooth muscle cells, vascular endothelial cells and pericytes-coordinate their activity to control this phenomenon. Recent work has revealed that ionic fluxes through a diverse array of ion channel species allow the cells of the neurovascular unit to engage in multicellular signaling processes that dictate local hemodynamics. In this review we center our discussion on two major themes: (1) the roles of ion channels in the dynamic modulation of parenchymal arteriole smooth muscle membrane potential, which is central to the control of arteriolar diameter and therefore must be harnessed to permit changes in downstream cerebral blood flow, and (2) the striking similarities in the ion channel complements employed in astrocytic endfeet and endothelial cells, enabling dual control of smooth muscle from either side of the blood-brain barrier. We conclude with a discussion of the emerging roles of pericyte and capillary endothelial cell ion channels in neurovascular coupling, which will provide fertile ground for future breakthroughs in the field.

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Intravascular pressure augments cerebral arterial constriction by inducing voltage-insensitive Ca²⁺waves

Cited by 59 publications

References 72 publications

Implications of α _v β ₃ Integrin Signaling in the Regulation of Ca ²⁺ Waves and Myogenic Tone in Cerebral Arteries

Implications of α _v β ₃ Integrin Signaling in the Regulation of Ca ²⁺ Waves and Myogenic Tone in Cerebral Arteries

The Role of Actin Filament Dynamics in the Myogenic Response of Cerebral Resistance Arteries

Ion channel networks in the control of cerebral blood flow

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Intravascular pressure augments cerebral arterial constriction by inducing voltage-insensitive Ca2+waves

Cited by 59 publications

References 72 publications

Implications of α v β 3 Integrin Signaling in the Regulation of Ca 2+ Waves and Myogenic Tone in Cerebral Arteries

Implications of α v β 3 Integrin Signaling in the Regulation of Ca 2+ Waves and Myogenic Tone in Cerebral Arteries

The Role of Actin Filament Dynamics in the Myogenic Response of Cerebral Resistance Arteries

Ion channel networks in the control of cerebral blood flow

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Product

Resources

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Intravascular pressure augments cerebral arterial constriction by inducing voltage-insensitive Ca²⁺waves

Implications of α _v β ₃ Integrin Signaling in the Regulation of Ca ²⁺ Waves and Myogenic Tone in Cerebral Arteries

Implications of α _v β ₃ Integrin Signaling in the Regulation of Ca ²⁺ Waves and Myogenic Tone in Cerebral Arteries