scholarly journals TNF-α dilates cerebral arteries via NAD(P)H oxidase-dependent Ca2+ spark activation

2006 ◽  
Vol 290 (4) ◽  
pp. C964-C971 ◽  
Author(s):  
Sergey Y. Cheranov ◽  
Jonathan H. Jaggar
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Laser Scanning ◽  
Channel Blocker ◽  
Cerebral Arteries ◽  
Muscle Cells ◽  
Confocal Imaging ◽  
Tnf Α ◽  
Intracellular Ca ◽  
Current Activation

Expression of TNF-α, a pleiotropic cytokine, is elevated during stroke and cerebral ischemia. TNF-α regulates arterial diameter, although mechanisms mediating this effect are unclear. In the present study, we tested the hypothesis that TNF-α regulates the diameter of resistance-sized (∼150-μm diameter) cerebral arteries by modulating local and global intracellular Ca2+ signals in smooth muscle cells. Laser-scanning confocal imaging revealed that TNF-α increased Ca2+ spark and Ca2+ wave frequency but reduced global intracellular Ca2+ concentration ([Ca2+]i) in smooth muscle cells of intact arteries. TNF-α elevated reactive oxygen species (ROS) in smooth muscle cells of intact arteries, and this increase was prevented by apocynin or diphenyleneiodonium (DPI), both of which are NAD(P)H oxidase blockers, but was unaffected by inhibitors of other ROS-generating enzymes. In voltage-clamped (−40 mV) cells, TNF-α increased the frequency and amplitude of Ca2+ spark-induced, large-conductance, Ca2+-activated K+ (KCa) channel transients ∼1.7- and ∼1.4-fold, respectively. TNF-α-induced transient KCa current activation was reversed by apocynin or by Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), a membrane-permeant antioxidant, and was prevented by intracellular dialysis of catalase. TNF-α induced reversible and similar amplitude dilations in either endothelium-intact or endothelium-denuded pressurized (60 mmHg) cerebral arteries. MnTMPyP, thapsigargin, a sarcoplasmic reticulum Ca2+-ATPase blocker that inhibits Ca2+ sparks, and iberiotoxin, a KCa channel blocker, reduced TNF-α-induced vasodilations to between 15 and 33% of control. In summary, our data indicate that TNF-α activates NAD(P)H oxidase, resulting in an increase in intracellular H2O2 that stimulates Ca2+ sparks and transient KCa currents, leading to a reduction in global [Ca2+]i, and vasodilation.

Intravascular pressure regulates local and global Ca2+ signaling in cerebral artery smooth muscle cells

2001 ◽  
Vol 281 (2) ◽  
pp. C439-C448 ◽  
Author(s):  
Jonathan H. Jaggar
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Laser Scanning ◽  
Muscle Cells ◽  
Membrane Depolarization ◽  
Wave Frequency ◽  
Current Frequency ◽  
Frequency Wave ◽  
Intracellular Ca ◽  
Intravascular Pressure

The regulation of intracellular Ca2+ signals in smooth muscle cells and arterial diameter by intravascular pressure was investigated in rat cerebral arteries (∼150 μm) using a laser scanning confocal microscope and the fluorescent Ca2+ indicator fluo 3. Elevation of pressure from 10 to 60 mmHg increased Ca2+spark frequency 2.6-fold, Ca2+ wave frequency 1.9-fold, and global intracellular Ca2+ concentration ([Ca2+]i) 1.4-fold in smooth muscle cells, and constricted arteries. Ryanodine (10 μM), an inhibitor of ryanodine-sensitive Ca2+ release channels, or thapsigargin (100 nM), an inhibitor of the sarcoplasmic reticulum Ca2+-ATPase, abolished sparks and waves, elevated global [Ca2+]i, and constricted pressurized (60 mmHg) arteries. Diltiazem (25 μM), a voltage-dependent Ca2+ channel (VDCC) blocker, significantly reduced sparks, waves, and global [Ca2+]i, and dilated pressurized (60 mmHg) arteries. Steady membrane depolarization elevated Ca2+ signaling similar to pressure and increased transient Ca2+-sensitive K+ channel current frequency e-fold for ∼7 mV, and these effects were prevented by VDCC blockers. Data are consistent with the hypothesis that pressure induces a steady membrane depolarization that activates VDCCs, leading to an elevation of spark frequency, wave frequency, and global [Ca2+]i. In addition, pressure induces contraction via an elevation of global [Ca2+]i, whereas the net effect of sparks and waves, which do not significantly contribute to global [Ca2+]i in arteries pressurized to between 10 and 60 mmHg, is to oppose contraction.

Effect of serotonin on intracellular free calcium of rat cerebrovascular smooth muscle cells in culture

1991 ◽  
Vol 69 (3) ◽  
pp. 393-399 ◽  
Author(s):  
Y. Wang ◽  
K. G. Baimbridge ◽  
D. A. Mathers
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Intracellular Calcium ◽  
Cerebral Arteries ◽  
Muscle Cells ◽  
Free Calcium ◽  
Adult Rats ◽  
Fura 2 ◽  
Free Intracellular Calcium ◽  
Intracellular Ca

Smooth muscle cells were dissociated from conducting cerebral arteries of adult rats and maintained in culture for 2–4 days. The calcium-sensitive fluorescent probe, fura-2, was used to study the effect of the vasoconstrictor serotonin (5-HT) on the level of free intracellular Ca2+ in these cells. The baseline level of free intracellular calcium was 39 ± 3.6 nM. In 74 out of 110 cells, 5-HT application transiently increased the free Ca2+ content. This effect was dose-dependent and was suppressed by nanomolar concentrations of the 5-HT2 receptor antagonist, ketanserin. The 5-HT induced rise in free intracellular calcium was not prevented by the presence of Co2+, La3+, or nifedipine, blockers of voltage-sensitive calcium channels. These results indicate that 5-HT mobilizes intracellular Ca2+ in cultured smooth muscle cells derived from the rat cerebrovasculature. The mobilization of intracellular Ca2+ appears to be triggered by a 5-HT2 type receptor, although further pharmacological experiments are required to verify this hypothesis.Key words: serotonin, smooth muscle, cerebral artery, intracellular calcium, fura-2.

scholarly journals Type 1 inositol 1,4,5-trisphosphate receptors mediate UTP-induced cation currents, Ca2+ signals, and vasoconstriction in cerebral arteries

2008 ◽  
Vol 295 (5) ◽  
pp. C1376-C1384 ◽  
Author(s):  
Guiling Zhao ◽  
Adebowale Adebiyi ◽  
Eva Blaskova ◽  
Qi Xi ◽  
Jonathan H. Jaggar
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cerebral Artery ◽  
Purinergic Receptor ◽  
Cerebral Arteries ◽  
Muscle Cells ◽  
Physiological Functions ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Ca

Inositol 1,4,5-trisphosphate receptors (IP3Rs) regulate diverse physiological functions, including contraction and proliferation. There are three IP3R isoforms, but their functional significance in arterial smooth muscle cells is unclear. Here, we investigated relative expression and physiological functions of IP3R isoforms in cerebral artery smooth muscle cells. We show that 2-aminoethoxydiphenyl borate and xestospongin C, membrane-permeant IP3R blockers, reduced Ca2+ wave activation and global intracellular Ca2+ ([Ca2+]i) elevation stimulated by UTP, a phospholipase C-coupled purinergic receptor agonist. Quantitative PCR, Western blotting, and immunofluorescence indicated that all three IP3R isoforms were expressed in acutely isolated cerebral artery smooth muscle cells, with IP3R1 being the most abundant isoform at 82% of total IP3R message. IP3R1 knockdown with short hairpin RNA (shRNA) did not alter baseline Ca2+ wave frequency and global [Ca2+]i but abolished UTP-induced Ca2+ wave activation and reduced the UTP-induced global [Ca2+]i elevation by ∼61%. Antibodies targeting IP3R1 and IP3R1 knockdown reduced UTP-induced nonselective cation current ( Icat) activation. IP3R1 knockdown also reduced UTP-induced vasoconstriction in pressurized arteries with both intact and depleted sarcoplasmic reticulum (SR) Ca2+ by ∼45%. These data indicate that IP3R1 is the predominant IP3R isoform expressed in rat cerebral artery smooth muscle cells. IP3R1 stimulation contributes to UTP-induced Icat activation, Ca2+ wave generation, global [Ca2+]i elevation, and vasoconstriction. In addition, IP3R1 activation constricts cerebral arteries in the absence of SR Ca2+ release by stimulating plasma membrane Icat.

Alkaline pH shifts Ca2+ sparks to Ca2+waves in smooth muscle cells of pressurized cerebral arteries

2002 ◽  
Vol 283 (6) ◽  
pp. H2169-H2176 ◽  
Author(s):  
Thomas J. Heppner ◽  
Adrian D. Bonev ◽  
L. Fernando Santana ◽  
Mark T. Nelson
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cerebral Arteries ◽  
Ryanodine Receptors ◽  
Muscle Cells ◽  
Alkaline Ph ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
A Minor ◽  
External Ph

The effects of external pH (7.0–8.0) on intracellular Ca2+ signals (Ca2+ sparks and Ca2+ waves) were examined in smooth muscle cells from intact pressurized arteries from rats. Elevating the external pH from 7.4 to 7.5 increased the frequency of local, Ca2+transients, or “Ca2+ sparks,” and, at pH 7.6, significantly increased the frequency of Ca2+ waves. Alkaline pH-induced Ca2+ waves were inhibited by blocking Ca2+ release from ryanodine receptors but were not prevented by inhibitors of voltage-dependent Ca2+ channels, phospholipase C, or inositol 1,4,5-trisphosphate receptors. Activating ryanodine receptors with caffeine (5 mM) at pH 7.4 also induced repetitive Ca2+ waves. Alkalization from pH 7.4 to pH 7.8–8.0 induced a rapid and large vasoconstriction. Approximately 82% of the alkaline pH-induced vasoconstriction was reversed by inhibitors of voltage-dependent Ca2+ channels. The remaining constriction was reversed by inhibition of ryanodine receptors. These findings indicate that alkaline pH-induced Ca2+ waves originate from ryanodine receptors and make a minor, direct contribution to alkaline pH-induced vasoconstriction.

Nucleoplasmic calcium regulation in rabbit aortic vascular smooth muscle cells

2003 ◽  
Vol 81 (3) ◽  
pp. 301-310 ◽  
Author(s):  
Bernard Abrenica ◽  
Grant N Pierce ◽  
James S.C Gilchrist
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Signal Intensity ◽  
Laser Scanning ◽  
Muscle Cells ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
Intracellular Ca

In this study, we investigated whether nucleoplasmic free Ca2+ in aortic vascular smooth muscle cells (VSMCs) might be independently regulated from cytosolic free Ca2+. Understanding mechanisms and pathways responsible for this regulation is especially relevant given the role of a numerous intranuclear Ca2+-sensitive proteins in transcriptional regulation, apoptosis and cell division. The question of an independent regulatory mechanism remains largely unsettled because the previous use of intensitometric fluorophores (e.g., Fluo-3) has been criticized on technical grounds. To circumvent the potential problem of fluorescence artifact, we utilized confocal laser scanning microscopy to image intracellular Ca2+ movements with the ratiometric fluorophore Indo-1. In cultured rabbit VSMCs, we found sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) pumps and ryanodine receptor (RyR) Ca2+ channel proteins to be discretely arranged within a perinuclear locus, as determined by fluorescent staining patterns of BODIPY® FL thapsi gargin and BODIPY® FL-X Ry. When intracellular Ca2+ stores were mobilized by addition of thapsigargin (5 μM) and activatory concentrations of ryanodine (1 μM), Indo-1 ratiometric signals were largely restricted to the nucleoplasm. Cytosolic signals, by comparison, were relatively small and even then its spatial distribution was largely perinuclear rather homogeneous. These observations indicate perinuclear RyR and SERCA proteins are intimately involved in regulating VSMC nucleoplasmic Ca2+ concentrations. We also observed a similar pattern of largely nucleoplasmic Ca2+ mobilization upon exposure of cells to the immunosuppressant drug FK506 (tacrolimus), which binds to the RyR-associated immunophillin-binding proteins FKBP12 and FKBP12.6. However, initial FK506-induced nucleoplasmic Ca2+ mobilization was followed by marked reduction of Indo-1 signal intensity close to pretreatment levels. This suggested FK506 exerts both activatory and inhibitory effects upon RyR channels. The latter was reinforced by observed effects of FK506 to only reduce nucleoplasmic Indo-1 signal intensity when added following pretreatment with both activatory and inhibitory concentrations of ryanodine. These latter observations raise the possibility that VSMC nuclei represent an important sink of intracellular Ca2+ and may help explain vasodilatory actions of FK506 observed by others.Key words: Ca2+, RyR, SERCA, cell nucleus, FK506, thapsigargin, ryanodine.

scholarly journals Caveolin-1 abolishment attenuates the myogenic response in murine cerebral arteries

2007 ◽  
Vol 292 (3) ◽  
pp. H1584-H1592 ◽  
Author(s):  
Adebowale Adebiyi ◽  
Guiling Zhao ◽  
Sergey Y. Cheranov ◽  
Abu Ahmed ◽  
Jonathan H. Jaggar
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Channel Blocker ◽  
Cerebral Arteries ◽  
Muscle Cells ◽  
Myogenic Tone ◽  
Myogenic Response ◽  
Arterial Smooth Muscle ◽  
Caveolin 1 ◽  
Intravascular Pressure

Intravascular pressure-induced vasoconstriction (the “myogenic response”) is intrinsic to smooth muscle cells, but mechanisms that underlie this response are unresolved. Here we investigated the physiological function of arterial smooth muscle cell caveolae in mediating the myogenic response. Since caveolin-1 (cav-1) ablation abolishes caveolae formation in arterial smooth muscle cells, myogenic mechanisms were compared in cerebral arteries from control (cav-1+/+) and cav-1-deficient (cav-1−/−) mice. At low intravascular pressure (10 mmHg), wall membrane potential, intracellular calcium concentration ([Ca2+]i), and myogenic tone were similar in cav-1+/+ and cav-1−/− arteries. In contrast, pressure elevations to between 30 and 70 mmHg induced a smaller depolarization, [Ca2+]i elevation, and myogenic response in cav-1−/− arteries. Depolarization induced by 60 mM K+ also produced an attenuated [Ca2+]i elevation and constriction in cav-1−/− arteries, whereas extracellular Ca2+ removal and diltiazem, an L-type Ca2+ channel blocker, similarly dilated cav-1+/+ and cav-1−/− arteries. Nω-nitro-l-arginine, an nitric oxide synthase inhibitor, did not restore myogenic tone in cav-1−/− arteries. Iberiotoxin, a selective Ca2+-activated K+ (KCa) channel blocker, induced a similar depolarization and constriction in pressurized cav-1+/+ and cav-1−/− arteries. Since pressurized cav-1−/− arteries are more hyperpolarized and this effect would reduce KCa current, these data suggest that cav-1 ablation leads to functional KCa channel activation, an effect that should contribute to the attenuated myogenic constriction. In summary, data indicate that cav-1 ablation reduces pressure-induced depolarization and depolarization-induced Ca2+ influx, and these effects combine to produce a diminished arterial wall [Ca2+]i elevation and constriction.

Microtubule-dependent PKC-α localization in A7r5 smooth muscle cells

2003 ◽  
Vol 285 (1) ◽  
pp. C76-C87 ◽  
Author(s):  
A. C. Dykes ◽  
M. E. Fultz ◽  
M. L. Norton ◽  
G. L. Wright
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Laser Scanning ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Muscle Cells ◽  
Confocal Imaging ◽  
Perinuclear Region ◽  
Dynamic Activity ◽  
Specialized Structure

Using laser scanning confocal, fluorescence resonance energy transfer (FRET), and atomic force (AFM) microscopy, we investigated association of protein kinase C (PKC)-α with microtubules during stimulus-induced relocalization in A7r5 smooth muscle cells. Confocal microscopy with standard immunostaining techniques confirmed earlier observations that colchicine disruption of microtubules blocked PKC-α localization in the perinuclear region of the cell caused by phorbol 12,13-dibutyrate (PDBu; 10–6M). Dual immunostaining suggested colocalization of PKC-α and β-tubulin in both unstimulated and PDBu-treated cells. This finding was verified by FRET microscopy, which indicated that association of PKC-α was heterogeneous in distribution and confined primarily to microtubules in the perinuclear region. FRET analysis further showed that association between the molecules was not lost during colchicine-induced dissolution of microtubules, suggesting formation of tubulin-PKC-α complexes in the cytosol. Confocal imaging indicated that perinuclear microtubular structure was more highly sensitive to colchicine dissolution than other regions of the cell. Topographic imaging of fixed cells by AFM indicated a well-defined elevated structure surrounding the nucleus that was absent in colchicine-treated cells. It was calculated that the volume of the nuclear sleevelike structure of microtubules increased approximately fivefold in PDBu-treated cells, suggesting a probable increase in microtubular mass. In light of PKC-α localization, increased colchicine sensitivity, and their volume change in stimulated cells, the results suggest that perinuclear microtubules form a specialized structure that may be more dynamically robust than in other regions of the cell. PKC-α could contribute to this dynamic activity. Alternatively, perinuclear microtubules could act as a scaffold for regulatory molecule interaction at the cell center.

Voltage dependence of Ca2+sparks in intact cerebral arteries

1998 ◽  
Vol 274 (6) ◽  
pp. C1755-C1761 ◽  
Author(s):  
Jonathan H. Jaggar ◽  
Andrá S. Stevenson ◽  
Mark T. Nelson
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Smooth Muscle Cells ◽  
Laser Scanning ◽  
Cerebral Arteries ◽  
Muscle Cells ◽  
Dependent Manner ◽  
Isolated Cells ◽  
Concentration Dependent Manner ◽  
Smooth Muscle Preparation

Ca2+ sparks have been previously described in isolated smooth muscle cells. Here we present the first measurements of local Ca2+ transients (“Ca2+ sparks”) in an intact smooth muscle preparation. Ca2+sparks appear to result from the opening of ryanodine-sensitive Ca2+ release (RyR) channels in the sarcoplasmic reticulum (SR). Intracellular Ca2+ concentration ([Ca2+]i) was measured in intact cerebral arteries (40–150 μm in diameter) from rats, using the fluorescent Ca2+ indicator fluo 3 and a laser scanning confocal microscope. Membrane potential depolarization by elevation of external K+ from 6 to 30 mM increased Ca2+ spark frequency (4.3-fold) and amplitude (∼2-fold) as well as global arterial wall [Ca2+]i(∼1.7-fold). The half time of decay (∼50 ms) was not affected by membrane potential depolarization. Ryanodine (10 μM), which inhibits RyR channels and Ca2+ sparks in isolated cells, and thapsigargin (100 nM), which indirectly inhibits RyR channels by blocking the SR Ca2+-ATPase, completely inhibited Ca2+ sparks in intact cerebral arteries. Diltiazem, an inhibitor of voltage-dependent Ca2+ channels, lowered global [Ca2+]iand Ca2+ spark frequency and amplitude in intact cerebral arteries in a concentration-dependent manner. The frequency of Ca2+sparks (<1 s−1 ⋅ cell−1), even under conditions of steady depolarization, was too low to contribute significant amounts of Ca2+ to global Ca2+ in intact arteries. These results provide direct evidence that Ca2+ sparks exist in quiescent smooth muscle cells in intact arteries and that changes of membrane potential that would simulate physiological changes modulate both Ca2+ spark frequency and amplitude in arterial smooth muscle.

Spatial and temporal aspects of calcium sparks in porcine tracheal smooth muscle cells

1999 ◽  
Vol 277 (5) ◽  
pp. L1018-L1025 ◽  
Author(s):  
Christina M. Pabelick ◽  
Y. S. Prakash ◽  
Mathur S. Kannan ◽  
Gary C. Sieck
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Temporal Integration ◽  
Muscle Cells ◽  
Confocal Imaging ◽  
Tracheal Smooth Muscle ◽  
Temporal Relationships ◽  
Temporal Aspects ◽  
Intracellular Ca ◽  
Intracellular Region

Spontaneous, localized intracellular Ca2+concentration ([Ca2+]i) transients (Ca2+ sparks) in skeletal, cardiac, and smooth muscle cells are thought to represent Ca2+ release through ryanodine-receptor (RyR) channels. In porcine tracheal smooth muscle (TSM) cells, ACh induces propagating [Ca2+]ioscillations that also represent Ca2+ release through RyR channels. We used real-time confocal imaging to examine the spatial and temporal relationships of Ca2+ sparks to propagating [Ca2+]ioscillations in TSM cells. Ca2+sparks within an intracellular region displayed different spatial Ca2+ distributions with every occurrence. The amplitudes of Ca2+sparks within a region were approximately integer multiples of the smallest response. However, across different regions, the attributes of Ca2+ sparks varied considerably. Individual sparks were often grouped together and coupled across adjacent regions. Fusion of individual sparks produced large local elevations in [Ca2+]ithat occasionally triggered a propagating [Ca2+]iwave. The incidence of sparks was increased by ryanodine and caffeine but was unaffected by removal of extracellular Ca2+. Exposure to ACh triggered repetitive, propagating [Ca2+]ioscillations that always originated from foci with a high spark incidence. The [Ca2+]ioscillations disappeared with the removal of ACh, and Ca2+ sparks reappeared. We conclude that agonist-induced [Ca2+]ioscillations represent a spatial and temporal integration of local Ca2+-release events through RyR channels in TSM cells.

scholarly journals Vasoconstriction resulting from dynamic membrane trafficking of TRPM4 in vascular smooth muscle cells

2010 ◽  
Vol 299 (3) ◽  
pp. C682-C694 ◽  
Author(s):  
Rachael Crnich ◽  
Gregory C. Amberg ◽  
M. Dennis Leo ◽  
Albert L. Gonzales ◽  
Michael M. Tamkun ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Plasma Membrane ◽  
Cell Surface ◽  
Smooth Muscle Cells ◽  
Membrane Trafficking ◽  
Transient Receptor Potential ◽  
Cerebral Arteries ◽  
Muscle Cells ◽  
Confocal Imaging ◽  
A7r5 Cells

The melastatin (M) transient receptor potential (TRP) channel TRPM4 mediates pressure and protein kinase C (PKC)-induced smooth muscle cell depolarization and vasoconstriction of cerebral arteries. We hypothesized that PKC causes vasoconstriction by stimulating translocation of TRPM4 to the plasma membrane. Live-cell confocal imaging and fluorescence recovery after photobleaching (FRAP) analysis was performed using a green fluorescent protein (GFP)-tagged TRPM4 (TRPM4-GFP) construct expressed in A7r5 cells. The surface channel was mobile, demonstrating a FRAP time constant of 168 ± 19 s. In addition, mobile intracellular trafficking vesicles were readily detected. Using a cell surface biotinylation assay, we showed that PKC activation with phorbol 12-myristate 13-acetate (PMA) increased (∼3-fold) cell surface levels of TRPM4-GFP protein in <10 min. Similarly, total internal reflection fluorescence microscopy demonstrated that stimulation of PKC activity increased (∼3-fold) the surface fluorescence of TRPM4-GFP in A7r5 cells and primary cerebral artery smooth muscle cells. PMA also caused an elevation of cell surface TRPM4 protein levels in intact arteries. PMA-induced translocation of TRPM4 to the plasma membrane was independent of PKCα and PKCβ activity but was inhibited by blockade of PKCδ with rottlerin. Pressure-myograph studies of intact, small interfering RNA (siRNA)-treated cerebral arteries demonstrate that PKC-induced constriction of cerebral arteries requires expression of both TRPM4 and PKCδ. In addition, pressure-induced arterial myocyte depolarization and vasoconstriction was attenuated in arteries treated with siRNA against PKCδ. We conclude that PKCδ activity causes smooth muscle depolarization and vasoconstriction by increasing the number of TRPM4 channels in the sarcolemma.

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