Effects of sudden transmural pressure elevation on myogenic tone and reactivity of WKY vs. SHRSP cerebral arteries in vitro

Gender is known to influence the incidence and severity of cerebrovascular disease. In the present study, luminal diameter was measured in vitro in pressurized middle cerebral artery segments from male rats that were either untreated, orchiectomized (ORX), ORX with testosterone treatment (ORX+TEST), or ORX with estrogen treatment (ORX+EST). The maximal passive diameters (0 Ca2+ + 3 mM EDTA) of arteries from all four groups were similar. In endothelium-intact arteries, myogenic tone was significantly greater in arteries from untreated and ORX+TEST compared with arteries from either ORX or ORX+EST. During exposure to N G-nitro-l-arginine-methyl ester (l-NAME), an NO synthase (NOS) inhibitor, myogenic tone significantly increased in all groups. The effect of l-NAME was significantly greater in arteries from untreated and ORX+EST compared with arteries from ORX and ORX+TEST rats. Differences in myogenic tone between ORX and ORX+TEST persisted after inhibition of NOS. After endothelium removal or inhibition of the cyclooxygenase pathway combined with K+ channel blockers, myogenic tone differences between ORX and ORX+TEST were abolished. Wall thickness and forced dilation were not significantly different between arteries from ORX and ORX+TEST. Our data show that gonadal hormones affect myogenic tone in male rat cerebral arteries through NOS- and/or endothelium-dependent mechanisms.

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Myogenic tone, reactivity, and forced dilatation: a three-phase model of in vitro arterial myogenic behavior

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00634.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. H2260-H2267 ◽

Cited By ~ 93

Author(s):

George Osol ◽

Johan Fredrik Brekke ◽

Keara McElroy-Yaggy ◽

Natalia I. Gokina

Keyword(s):

Cerebral Arteries ◽

Peripheral Resistance ◽

Force Production ◽

Cytosolic Calcium ◽

Myogenic Tone ◽

Wall Tension ◽

Resistance Arteries ◽

Cellular Mechanisms ◽

Initial Development

Myogenic behavior, prevalent in resistance arteries and arterioles, involves arterial constriction in response to intravascular pressure. This process is often studied in vitro by using cannulated, pressurized arterial segments from different regional circulations. We propose a comprehensive model for myogenicity that consists of three interrelated but dissociable phases: 1) the initial development of myogenic tone (MT), 2) myogenic reactivity to subsequent changes in pressure (MR), and 3) forced dilatation at high transmural pressures (FD). The three phases span the physiological range of transmural pressures (e.g., MT, 40–60 mmHg; MR, 60–140 mmHg; FD, >140 mmHg in cerebral arteries) and are characterized by distinct changes in cytosolic calcium ([Ca2+]i), which do not parallel arterial diameter or wall tension, and therefore suggest the existence of additional regulatory mechanisms. Specifically, the development of MT is accompanied by a substantial (200%) elevation in [Ca2+]i and a reduction in lumen diameter and wall tension, whereas MR is associated with relatively small [Ca2+]i increments (<20% over the entire pressure range) despite considerable increases in wall tension and force production but little or no change in diameter. FD is characterized by a significant additional elevation in [Ca2+]i (>50%), complete loss of force production, and a rapid increase in wall tension. The utility of this model is that it provides a framework for comparing myogenic behavior of vessels of different size and anatomic origin and for investigating the underlying cellular mechanisms that govern vascular smooth muscle mechanotransduction and contribute to the regulation of peripheral resistance.

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Enhanced myogenic tone in cerebral arteries from a rabbit model of subarachnoid hemorrhage

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00629.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. H2217-H2225 ◽

Cited By ~ 37

Author(s):

Masanori Ishiguro ◽

Corey B. Puryear ◽

Erica Bisson ◽

Christine M. Saundry ◽

David J. Nathan ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Artery ◽

Cerebral Arteries ◽

Rabbit Model ◽

Small Diameter ◽

Myogenic Tone ◽

The Impact ◽

Intravascular Pressure

Cerebral artery vasospasm is a major cause of death and disability in patients experiencing subarachnoid hemorrhage (SAH). Currently, little is known regarding the impact of SAH on small diameter (100–200 μm) cerebral arteries, which play an important role in the autoregulation of cerebral blood flow. With the use of a rabbit SAH model and in vitro video microscopy, cerebral artery diameter was measured in response to elevations in intravascular pressure. Cerebral arteries from SAH animals constricted more (∼twofold) to pressure within the physiological range of 60–100 mmHg compared with control or sham-operated animals. Pressure-induced constriction (myogenic tone) was also enhanced in arteries from control animals organ cultured in the presence of oxyhemoglobin, an effect independent of the vascular endothelium or nitric oxide synthesis. Finally, arteries from both control and SAH animals dilated as intravascular pressure was elevated above 140 mmHg. This study provides evidence for a role of oxyhemoglobin in impaired autoregulation (i.e., enhanced myogenic tone) in small diameter cerebral arteries during SAH. Furthermore, therapeutic strategies that improve clinical outcome in SAH patients (e.g., supraphysiological intravascular pressure) are effective in dilating small diameter cerebral arteries isolated from SAH animals.

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Circadian Rhythmicity in Cerebral Microvascular Tone Influences Subarachnoid Hemorrhage–Induced Injury

Stroke ◽

10.1161/strokeaha.121.036950 ◽

2021 ◽

Author(s):

Darcy Lidington ◽

Hoyee Wan ◽

Danny D. Dinh ◽

Chloe Ng ◽

Steffen-Sebastian Bolz

Keyword(s):

Smooth Muscle ◽

Subarachnoid Hemorrhage ◽

Circadian Rhythms ◽

Cerebral Arteries ◽

Circadian Variation ◽

Neurological Injury ◽

Myogenic Tone ◽

Resistance Arteries

Background and Purpose: Circadian rhythms influence the extent of brain injury following subarachnoid hemorrhage (SAH), but the mechanism is unknown. We hypothesized that cerebrovascular myogenic reactivity is rhythmic and explains the circadian variation in SAH-induced injury. Methods: SAH was modeled in mice with prechiasmatic blood injection. Inducible, smooth muscle cell–specific Bmal1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1) gene deletion (smooth muscle–specific Bmal1 1 knockout [sm-Bmal1 KO]) disrupted circadian rhythms within the cerebral microcirculation. Olfactory cerebral resistance arteries were functionally assessed by pressure myography in vitro; these functional assessments were related to polymerase chain reaction/Western blot data, brain histology (Fluoro-Jade/activated caspase-3), and neurobehavioral assessments (modified Garcia scores). Results: Cerebrovascular myogenic vasoconstriction is rhythmic, with a peak and trough at Zeitgeber times 23 and 11 (ZT23 and ZT11), respectively. Histological and neurobehavioral assessments demonstrate that higher injury levels occur when SAH is induced at ZT23, compared with ZT11. In sm-Bmal1 KO mice, myogenic reactivity is not rhythmic. Interestingly, myogenic tone is higher at ZT11 versus ZT23 in sm-Bmal1 KO mice; accordingly, SAH-induced injury in sm-Bmal1 KO mice is more severe when SAH is induced at ZT11 compared to ZT23. We examined several myogenic signaling components and found that CFTR (cystic fibrosis transmembrane conductance regulator) expression is rhythmic in cerebral arteries. Pharmacologically stabilizing CFTR expression in vivo (3 mg/kg lumacaftor for 2 days) eliminates the rhythmicity in myogenic reactivity and abolishes the circadian variation in SAH-induced neurological injury. Conclusions: Cerebrovascular myogenic reactivity is rhythmic. The level of myogenic tone at the time of SAH ictus is a key factor influencing the extent of injury. Circadian oscillations in cerebrovascular CFTR expression appear to underlie the cerebrovascular myogenic reactivity rhythm.

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Estrogen reduces myogenic tone through a nitric oxide-dependent mechanism in rat cerebral arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.275.1.h292 ◽

1998 ◽

Vol 275 (1) ◽

pp. H292-H300 ◽

Cited By ~ 35

Author(s):

Greg G. Geary ◽

Diana N. Krause ◽

Sue P. Duckles

Keyword(s):

Nitric Oxide ◽

Cerebral Arteries ◽

Myogenic Tone ◽

No Production ◽

Luminal Diameter ◽

Underlying Mechanisms ◽

Synthase Inhibitor ◽

Endothelial Nitric Oxide ◽

Dependent Mechanism

Gender differences in the incidence of stroke and migraine appear to be related to circulating levels of estrogen; however, the underlying mechanisms are not yet understood. Using resistance-sized arteries pressurized in vitro, we have found that myogenic tone of rat cerebral arteries differs between males and females. This difference appears to result from estrogen enhancement of endothelial nitric oxide (NO) production. Luminal diameter was measured in middle cerebral artery segments from males and from females that were either untreated, ovariectomized (Ovx), or ovariectomized with estrogen replacement (Ovx + Est). The maximal passive diameters (0 Ca2++ 1 mM EDTA) of arteries from all four groups were identical. In response to a series of 10-mmHg step increases in transmural pressure (20–80 mmHg), myogenic tone was greater and vascular distensibility less in arteries from males and Ovx females compared with arteries from either untreated or Ovx + Est females. In the presence of N G-nitro-l-arginine methyl ester (l-NAME; 1 μM), an NO synthase inhibitor, myogenic tone was increased in all arteries, but the differences among arteries from the various groups were abolished. Addition ofl-arginine (1 mM) in the presence of l-NAME restored the differences in myogenic tone, suggesting that estrogen works through an NO-dependent mechanism in cerebral arteries. To determine the target of NO-dependent modulation of myogenic tone, we used tetraethylammonium (TEA; 1 mM) to inhibit large-conductance, calcium-activated K+(BKCa) channels. In the presence of TEA, the myogenic tone of arteries from all groups increased significantly; however, myogenic tone in arteries from males and Ovx females remained significantly greater than in arteries from either untreated or Ovx + Est females. This suggests that activity of BKCa channels influences myogenic tone but does not directly mediate the effects of estrogen. Estrogen appears to alter myogenic tone by increasing cerebrovascular NO production and/or action.

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Myogenic properties of cerebral blood vessels from normotensive and hypertensive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1985.249.5.h914 ◽

1985 ◽

Vol 249 (5) ◽

pp. H914-H921 ◽

Cited By ~ 54

Author(s):

G. Osol ◽

W. Halpern

Keyword(s):

Spontaneously Hypertensive Rat ◽

Cerebral Arteries ◽

Physiological Saline ◽

Transmural Pressure ◽

Hypertensive Rats ◽

Pressure Step ◽

Wide Range ◽

Myogenic Responses ◽

Wistar Kyoto

Myogenic properties of posterior cerebral arteries from normotensive and hypertensive rats were analyzed in vitro and quantified in terms of both pressure range limits and degree of myogenic activity. Spontaneously hypertensive rat (SHR) vessels were significantly narrower in a fully relaxed state, and both wall thickness and wall-to-radius ratios were increased. After equilibration in 1.6 mM calcium physiological saline solution a substantial tone developed which resulted in average diameter decreases of 34 and 37% in Wistar-Kyoto (WKY) and SHR, respectively; average lumen diameters were approximately 125 micron. Rapid changes in transmural pressure (delta P 10-25 mmHg/s) were applied and diameter responses measured continuously. Myogenic responses began 1-3 s after a change in transmural pressure, and arteries regained their initial diameters after a pressure step in about 2 min; a final, steady-state diameter was achieved in 4-5 min. Myogenic pressure ranges were 49-145 mmHg in WKY and 64-181 in SHR; when responses were segregated according to positive and negative pressure steps, more myogenic responses were observed at lower pressures for pressure step decreases when compared with pressure step increases. Thus myogenic ranges for increasing pressure steps were 71-151 (WKY) and 72-188 mmHg (SHR) and for decreasing steps 45-117 (WKY) and 57-148 mmHg (SHR). Myogenic responses in SHR were weaker than in WKY rats: the former maintained essentially a constant diameter over a wide range of pressures, whereas arteries from the latter decreased diameter with increasing pressures.(ABSTRACT TRUNCATED AT 250 WORDS)

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Regulation of arterial tone by smooth muscle myosin type II

AJP Cell Physiology ◽

10.1152/ajpcell.01369.2000 ◽

2002 ◽

Vol 283 (5) ◽

pp. C1383-C1389 ◽

Cited By ~ 11

Author(s):

Matthias Löhn ◽

Dietmar Kämpf ◽

Chai Gui-Xuan ◽

Hermann Haller ◽

Friedrich C. Luft ◽

...

Keyword(s):

Smooth Muscle ◽

Molecular Motor ◽

Cerebral Arteries ◽

Motor Protein ◽

Myogenic Tone ◽

Type Ii ◽

Pressure Elevation ◽

Intracellular Ca ◽

Myosin Type Ii ◽

Type Ii Myosin

The initiation of contractile force in arterial smooth muscle (SM) is believed to be regulated by the intracellular Ca2+concentration and SM myosin type II phosphorylation. We tested the hypothesis that SM myosin type II operates as a molecular motor protein in electromechanical, but not in protein kinase C (PKC)-induced, contraction of small resistance-sized cerebral arteries. We utilized a SM type II myosin heavy chain (MHC) knockout mouse model and measured arterial wall Ca2+ concentration ([Ca2+]i) and the diameter of pressurized cerebral arteries (30–100 μm) by means of digital fluorescence video imaging. Intravasal pressure elevation caused a graded [Ca2+]i increase and constricted cerebral arteries of neonatal wild-type mice by 20–30%. In contrast, intravasal pressure elevation caused a graded increase of [Ca2+]i without constriction in (−/−) MHC-deficient arteries. KCl (60 mM) induced a further [Ca2+]i increase but failed to induce vasoconstriction of (−/−) MHC-deficient cerebral arteries. Activation of PKC by phorbol ester (phorbol 12-myristate 13-acetate, 100 nM) induced a strong, sustained constriction of (−/−) MHC-deficient cerebral arteries without changing [Ca2+]i. These results demonstrate a major role for SM type II myosin in the development of myogenic tone and Ca2+-dependent constriction of resistance-sized cerebral arteries. In contrast, the sustained contractile response did not depend on myosin and intracellular Ca2+ but instead depended on PKC. We suggest that SM myosin type II operates as a molecular motor protein in the development of myogenic tone but not in pharmacomechanical coupling by PKC in cerebral arteries. Thus PKC-dependent phosphorylation of cytoskeletal proteins may be responsible for sustained contraction in vascular SM.

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Mechanical Properties of Rat Middle Cerebral Arteries With and Without Myogenic Tone

Journal of Biomechanical Engineering ◽

10.1115/1.1645525 ◽

2004 ◽

Vol 126 (1) ◽

pp. 76-81 ◽

Cited By ~ 13

Author(s):

Rebecca J. Coulson ◽

Marilyn J. Cipolla ◽

Lisa Vitullo ◽

Naomi C. Chesler

Keyword(s):

Vessel Wall ◽

Cerebral Arteries ◽

Passive State ◽

Myogenic Tone ◽

Drug Induced ◽

Elasticity Parameter ◽

Wall Stiffness ◽

Middle Cerebral Arteries ◽

Inner Diameter

The inner diameter and wall thickness of rat middle cerebral arteries (MCAs) were measured in vitro in both a pressure-induced, myogenically-active state and a drug-induced, passive state to quantify active and passive mechanical behavior. Elasticity parameters from the literature (stiffness derived from an exponential pressure-diameter relationship, β, and elasticity in response to an increment in pressure, Einc-p) and a novel elasticity parameter in response to smooth muscle cell (SMC) activation, Einc-a, were calculated. β for all passive MCAs was 9.11±1.07 but could not be calculated for active vessels. The incremental stiffness increased significantly with pressure in passive vessels; Einc-p 106 dynes/cm2 increased from 5.6±0.5 at 75 mmHg to 14.7±2.4 at 125 mmHg, (p<0.05). In active vessels, Einc-p 106 dynes/cm2 remained relatively constant (5.5±2.4 at 75 mmHg and 6.2±1.0 at 125 mmHg). Einc-a 106 dynes/cm2 increased significantly with pressure (from 15.1±2.3 at 75 mmHg to 49.4±12.6 at 125 mmHg, p<0.001), indicating a greater contribution of SMC activity to vessel wall stiffness at higher pressures.

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Interaction of myogenic mechanisms and hypoxic dilation in rat middle cerebral arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00635.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. H2276-H2281 ◽

Cited By ~ 11

Author(s):

Yanping Liu ◽

David R. Harder ◽

Julian H. Lombard

Keyword(s):

Transmembrane Potential ◽

Cerebral Arteries ◽

Vessel Diameter ◽

Transmural Pressure ◽

Sprague Dawley ◽

Pressure Elevation ◽

Sprague Dawley Rats ◽

Middle Cerebral Arteries ◽

Arterial Dilation ◽

Myogenic Responses

The goal of this study was to determine how myogenic responses and vascular responses to reduced Po 2 interact to determine vascular smooth muscle (VSM) transmembrane potential and active tone in isolated middle cerebral arteries from Sprague-Dawley rats. Stepwise elevation of transmural pressure led to depolarization of the VSM cells and myogenic constriction, and reduction of the O2concentration of the perfusion and superfusion reservoirs from 21% O2 to 0% O2 caused vasodilation and VSM hyperpolarization. Myogenic constriction and VSM depolarization in response to transmural pressure elevation still occurred at reduced Po 2. Arterial dilation in response to reduced Po 2 was not impaired by pressure elevation but was significantly reduced at the lowest transmural pressure (60 mmHg). However, the magnitude of VSM hyperpolarization was unaffected by transmural pressure elevation. This study demonstrates that myogenic activation in response to transmural pressure elevation does not override hypoxic relaxation of middle cerebral arteries and that myogenic responses and hypoxic relaxation can independently regulate vessel diameter despite substantial changes in the other variable.

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Role of iPLA2 and store-operated channels in agonist-induced Ca2+ influx and constriction in cerebral, mesenteric, and carotid arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01148.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. H1183-H1187 ◽

Cited By ~ 39

Author(s):

Kristen M. Park ◽

Mario Trucillo ◽

Nicolas Serban ◽

Richard A. Cohen ◽

Victoria M. Bolotina

Keyword(s):

Carotid Arteries ◽

Cerebral Arteries ◽

Present Evidence ◽

Voltage Gated ◽

Functional Inhibition ◽

Intracellular Ca ◽

Dependent Pathway ◽

Secondary Activation

Store-operated channels (SOC) and store-operated Ca2+ entry are known to play a major role in agonist-induced constriction of smooth muscle cells (SMC) in conduit vessels. In microvessels the role of SOC remains uncertain, in as much as voltage-gated L-type Ca2+ (CaL2+) channels are thought to be fully responsible for agonist-induced Ca2+ influx and vasoconstriction. We present evidence that SOC and their activation via a Ca2+-independent phospholipase A2 (iPLA2)-mediated pathway play a crucial role in agonist-induced constriction of cerebral, mesenteric, and carotid arteries. Intracellular Ca2+ in SMC and intraluminal diameter were measured simultaneously in intact pressurized vessels in vitro. We demonstrated that 1) Ca2+ and contractile responses to phenylephrine (PE) in cerebral and carotid arteries were equally abolished by nimodipine (a CaL2+ inhibitor) and 2-aminoethyl diphenylborinate (an inhibitor of SOC), suggesting that SOC and CaL2+ channels may be involved in agonist-induced constriction of cerebral arteries, and 2) functional inhibition of iPLA2β totally inhibited PE-induced Ca2+ influx and constriction in cerebral, mesenteric, and carotid arteries, whereas K+-induced Ca2+ influx and vasoconstriction mediated by CaL2+ channels were not affected. Thus iPLA2-dependent activation of SOC is crucial for agonist-induced Ca2+ influx and vasoconstriction in cerebral, mesenteric, and carotid arteries. We propose that, on PE-induced depletion of Ca2+ stores, nonselective SOC are activated via an iPLA2-dependent pathway and may produce a depolarization of SMC, which could trigger a secondary activation of CaL2+ channels and lead to Ca2+ entry and vasoconstriction.

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