Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells

2002 ◽  
Vol 282 (2) ◽  
pp. G226-G232 ◽  
Author(s):  
Hirotada Akiho ◽  
Patricia Blennerhassett ◽  
Yikang Deng ◽  
Stephen M. Collins
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Trichinella Spiralis ◽  
Muscle Cells ◽  
Dependent Manner ◽  
T Helper ◽  
Concentration Dependent Manner ◽  
T Helper 2 ◽  
Muscularis Externa

T helper 2 (Th2) cytokines interleukin (IL)-4 and IL-13, which activate signal transducer and activator of transcription 6 (STAT6) are expressed in the muscularis externa during nematode infection and are candidate mediators of the associated hypercontractility. To determine the locus of action of these cytokines, we examined the IL-4- and IL-13-induced hypercontractility of the isolated muscle cells from STAT6 +/+ and STAT6 −/− mice. We compared the results with cells isolated from Trichinella spiralis-infected STAT6 +/+ and STAT6 −/− mice. Carbamylcholine chloride (Carbachol) induced the contraction of jejunal muscle cells in a concentration-dependent manner maximal contraction (Rmax26.7 ± 1.9%). Cells from T. spiralis-infected STAT6 −/− mice showed the hypertrophy (cell lengths 41.4 ± 0.8 to 89.0 ± 8.7 μm) and hypercontractility (Rmax37.5 ± 1.3%) induced by infection. IL-4Rα mRNA was detected in dispersed smooth muscle cells. Incubation of longitudinal muscle-myenteric plexus (LMMP) with IL-4 and IL-13 enhanced Carbachol-induced muscle contraction (Rmax35.5 ± 1.9 and 32.4 ± 2.9%, respectively). Incubation of LMMP from STAT6 −/− mice with IL-4 did not enhance the contraction. The hypercontractility in T. spiralis-infected mice was attenuated in STAT6 −/− mice ( P < 0.02). These results indicate both IL-4 and IL-13 induce hypercontractility of muscle cells via the STAT6 pathway, and this is the basis for hypercontractility observed in T. spiralis-infected mice.

Differential blockade of agonist- and depolarization-induced 45Ca2+ influx in smooth muscle cells

1989 ◽  
Vol 257 (4) ◽  
pp. C607-C611 ◽  
Author(s):  
A. Wallnofer ◽  
C. Cauvin ◽  
T. W. Lategan ◽  
U. T. Ruegg
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle ◽  
Gamma S ◽  
Ca2 Channels ◽  
Stimulation Of

ATP stimulated 45Ca2+ influx in rat aortic smooth muscle cells in a concentration-dependent manner (EC50 = 3.6 +/- 0.5 X 10(-7) M). ADP and GTP were less effective than ATP in stimulating 45Ca2+ influx; AMP was weakly active and the adenosine agonist 5'-(N-ethyl-carboxamido)-adenosine (NECA) had no effect. ATP gamma S was about equieffective with ATP, whereas alpha,beta-methylene-ATP (APCPP) did not induce 45Ca2+ influx. Stimulation of 45Ca2+ influx by ATP was not abolished by the dihydropyridine Ca2+ channel antagonist darodipine (PY 108-068), which completely blocked depolarization-induced 45Ca2+ influx. Inorganic cations (La3+, Cd2+, Co2+, Ni2+, Mn2+, and Mg2+) were able to inhibit both agonist- and depolarization-induced 45Ca2+ influx. Cd2+, however, was approximately 20 times more selective in blocking K+-stimulated than agonist-stimulated 45Ca2+ influx. These data indicate that ATP-stimulated Ca2+ influx in rat aortic smooth muscle cells is resistant to darodipine but is reduced by La3+, Cd2+, and other inorganic blockers of Ca2+ channels.

scholarly journals The contribution of inositol 1,4,5-trisphosphate and ryanodine receptors to agonist-induced Ca2+ signaling of airway smooth muscle cells

2009 ◽  
Vol 297 (2) ◽  
pp. L347-L361 ◽  
Author(s):  
Yan Bai ◽  
Martin Edelmann ◽  
Michael J. Sanderson
Keyword(s):  
Wave Propagation ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Airway Smooth Muscle ◽  
Ryanodine Receptors ◽  
Muscle Cells ◽  
Airway Smooth Muscle Cells ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Inositol 1,4,5 Trisphosphate

The relative contribution of inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) and ryanodine receptors (RyRs) to agonist-induced Ca2+ signaling in mouse airway smooth muscle cells (SMCs) was investigated in lung slices with phase-contrast or laser scanning microscopy. At room temperature (RT), methacholine (MCh) or 5-hydroxytryptamine (5-HT) induced Ca2+ oscillations and an associated contraction in small airway SMCs. The subsequent exposure to an IP3R antagonist, 2-aminoethoxydiphenyl borate (2-APB), inhibited the Ca2+ oscillations and induced airway relaxation in a concentration-dependent manner. 2-APB also inhibited Ca2+ waves generated by the photolytic release of IP3. However, the RyR antagonist ryanodine had no significant effect, at any concentration, on airway contraction or agonist- or IP3-induced Ca2+ oscillations or Ca2+ wave propagation. By contrast, a second RyR antagonist, tetracaine, relaxed agonist-contracted airways and inhibited agonist-induced Ca2+ oscillations in a concentration-dependent manner. However, tetracaine did not affect IP3-induced Ca2+ release or wave propagation nor the Ca2+ content of SMC Ca2+ stores as evaluated by Ca2+-release induced by caffeine. Conversely, both ryanodine and tetracaine completely blocked agonist-independent slow Ca2+ oscillations induced by KCl. The inhibitory effects of 2-APB and absence of an effect of ryanodine on MCh-induced airway contraction or Ca2+ oscillations of SMCs were also observed at 37°C. In Ca2+-permeable SMCs, tetracaine inhibited agonist-induced contraction without affecting intracellular Ca2+ levels indicating that relaxation also resulted from a reduction in Ca2+ sensitivity. These results indicate that agonist-induced Ca2+ oscillations in mouse small airway SMCs are primary mediated via IP3Rs and that tetracaine induces relaxation by both decreasing Ca2+ sensitivity and inhibiting agonist-induced Ca2+ oscillations via an IP3-dependent mechanism.

Cocaine Induces Apoptosis in Primary Cultured Rat Aortic Vascular Smooth Muscle Cells: Possible Relationship to Aortic Dissection, Atherosclerosis, and Hypertension

2004 ◽  
Vol 23 (4) ◽  
pp. 233-237 ◽  
Author(s):  
Jialin Su ◽  
Jianfeng Li ◽  
Wenyan Li ◽  
Bella T. Altura ◽  
Burton M. Altura
Keyword(s):  
Smooth Muscle ◽  
Aortic Dissection ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Cocaine Abuse ◽  
Cardiovascular Effects ◽  
Muscle Cells ◽  
Dependent Manner ◽  
Concentration Dependent Manner

Cocaine abuse is known to induce many adverse cardiovascular effects, including hypertension, atherosclerosis, and aortic dissection. A major physiological event leading to these pathophysiological actions of cocaine could be apoptosis. This study was designed to investigate if primary cultured rat aortic vascular smooth muscle cells (VSMCs) can undergo apoptosis when treated with cocaine. After treatment with cocaine (10−6 to 10−4 M), morphological analysis of aortic VSMCs using confocal fluoresence microscopy showed that the percentage of apoptotic aortic VSMCs increased after cocaine (10−6 to 10−4 M) treatment for 12, 24, and 48 h. These results demonstrate that aortic VSMCs can undergo rapid apoptosis in response to cocaine in a concentration-dependent manner. Cocaine-induced apoptosis may thus play a major role in cocaine abuse-induced aortic dissection, atherosclerosis, and hypertension.

Regulation of glucose transport in aortic smooth muscle cells by cAMP and cGMP

2001 ◽  
Vol 353 (3) ◽  
pp. 513-519 ◽  
Author(s):  
Christopher J. MacKENZIE ◽  
Jill M. WAKEFIELD ◽  
Fiona CAIRNS ◽  
Anna F. DOMINICZAK ◽  
Gwyn W. GOULD
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Smooth Muscle Cells ◽  
Primary Cultures ◽  
Muscle Cells ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Common Element ◽  
Dependent Manner ◽  
Concentration Dependent Manner

We have studied the ability of cGMP and cAMP to modulate platelet-derived growth factor (PDGF)-stimulated 2-deoxy-d-glucose (deGlc) transport in primary cultures of vascular smooth muscle cells (VMSC) from rat aorta. PDGF stimulated deGlc transport in a time- and concentration-dependent manner. 8-Bromo-cGMP and atrial natriuretic peptide(1–28) [ANP(1–28)] were found to reduce PDGF-stimulated deGlc transport without affecting basal (unstimulated) transport activity. In contrast, 8-bromo-cAMP and dibutyryl-cAMP stimulated basal deGlc transport 2-fold and were without effect on PDGF-stimulated deGlc transport. 8-Bromo-cGMP also inhibited 8-bromo-cAMP-stimulated deGlc transport. The stimulation of deGlc transport by PDGF was sensitive to the mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase (MEK) inhibitor PD98059, and we show that ERK1/2 was activated by PDGF. Neither 8-bromo-cGMP nor ANP(1–28) inhibited PDGF-stimulated ERK activation, suggesting that the effects of cGMP and ANP(1–28) were not mediated by inhibition of this kinase. Our data also argue against a role for cGMP-dependent protein kinase in mediating the effects of cGMP or ANP(1–28). Collectively, our data suggest that in VSMC: (i) cGMP and cAMP have opposing effects on deGlc transport; (ii) PDGF and cAMP have common elements in the pathways by which they activate deGlc transport; and (iii) a common element may be the target of the cGMP-mediated inhibition of deGlc transport.

scholarly journals The Modulatory Effect of Ischemia and Reperfusion on Arginine Vasopressin-Induced Arterial Reactions

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Katarzyna Szadujkis-Szadurska ◽  
Bartosz Malinowski ◽  
Małgorzata Piotrowska ◽  
Grzegorz Grześk ◽  
Michał Wiciński ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Arginine Vasopressin ◽  
Muscle Cells ◽  
Signalling Pathway ◽  
Ischemia And Reperfusion ◽  
Dependent Manner ◽  
Male Wistar Rats ◽  
The Impact

Aim of the Study.The purpose of this study was to investigate the impact of ischemia and reperfusion on the resistance of arteries to AVP (arginine vasopressin), with a particular emphasis on the role of smooth muscle cells in the action of vasopressin receptors and the role of the cGMP-associated signalling pathway.Materials and Methods.Experiment was performed on the perfunded tail arteries from male Wistar rats. The constriction triggered by AVP after 30 minutes of ischemia and 30 and 90 minutes of reperfusion was analysed. Analogous experiments were also carried out in the presence of 8Br-cGMP.Results.Ischemia reduces and reperfusion increases in a time-dependent manner the arterial reaction to AVP. The presence of 8Br-cGMP causes a significant decrease of arterial reactivity under study conditions.Conclusions.Ischemia and reperfusion modulate arterial contraction triggered by AVP. The effect of 8Br-cGMP on reactions, induced by AVP after ischemia and reperfusion, indicates that signalling pathway associated with nitric oxide (NO) and cGMP regulates the tension of the vascular smooth muscle cells.

scholarly journals Endothelium-independent, ouabain-sensitive relaxation of bovine coronary arteries by EETs

2001 ◽  
Vol 280 (3) ◽  
pp. H1113-H1121 ◽  
Author(s):  
Phillip F. Pratt ◽  
Pinlan Li ◽  
Cecilia J. Hillard ◽  
Jason Kurian ◽  
William B. Campbell
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Potassium Chloride ◽  
Coronary Arteries ◽  
Muscle Tone ◽  
Muscle Cells ◽  
Resting Membrane Potential ◽  
Dependent Manner ◽  
Independent Manner ◽  
Concentration Dependent Manner

Endothelium-derived hyperpolarizing factor (EDHF) is released in response to agonists such as ACh and bradykinin and regulates vascular smooth muscle tone. Several studies have indicated that ouabain blocks agonist-induced, endothelium-dependent hyperpolarization of smooth muscle. We have demonstrated that epoxyeicosatrienoic acids (EETs), cytochrome P-450 metabolites of arachidonic acid, function as EDHFs. To further test the hypothesis that EETs represent EDHFs, we have examined the effects of ouabain on the electrical and mechanical effects of 14,15- and 11,12-EET in bovine coronary arteries. These arteries are relaxed in a concentration-dependent manner to 14,15- and 11,12-EET (EC50 = 6 × 10−7 M), bradykinin (EC50 = 1 × 10−9 M), sodium nitroprusside (SNP; EC50 = 2 × 10−7 M), and bimakalim (BMK; EC50 = 1 × 10−7 M). 11,12-EET-induced relaxations were identical in vessels with and without an endothelium. Potassium chloride (1–15 × 10−3 M) inhibited [3H]ouabain binding to smooth muscle cells but failed to relax the arteries. Ouabain (10−5 to 10−4 M) increased basal tone and inhibited the relaxations to bradykinin, 11,12-EET, and 14,15-EET, but not to SNP or BMK. Barium (3 × 10−5 M) did not alter EET-induced relaxations and ouabain plus barium was similar to ouabain alone. Resting membrane potential ( E m) of isolated smooth muscle cells was −50.2 ± 0.5 mV. Ouabain (3 × 10−5 and 1 × 10−4 M) decreased E m(−48.4 ± 0.2 mV), whereas 11,12-EET (10−7 M) increased E m (−59.2 ± 2.2 mV). Ouabain inhibited the 11,12-EET-induced increase in E m. In cell-attached patch clamp studies, 11,12-EET significantly increased the open-state probability ( NP o) of a calcium-activated potassium channel compared with control cells (0.26 ± 0.06 vs. 0.02 ± 0.01). Ouabain did not change NP o but blocked the 14,15-EET-induced increase in NP o. These results indicate that: 1) EETs relax coronary arteries in an endothelium-independent manner, 2) unlike EETs, potassium chloride does not relax the coronary artery, and 3) ouabain inhibits bradykinin- and EET-induced relaxations as has been reported for EDHF. These findings provide further evidence that EETs are EDHFs.

Pioglitazone attenuates hypertension and inhibits growth of renal arteriolar smooth muscle in rats

1993 ◽  
Vol 265 (4) ◽  
pp. R726-R732 ◽  
Author(s):  
R. K. Dubey ◽  
H. Y. Zhang ◽  
S. R. Reddy ◽  
M. A. Boegehold ◽  
T. A. Kotchen
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Calf Serum ◽  
Muscle Cells ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
In Vitro Proliferation ◽  
Concentration Dependent Manner ◽  
Blood Pressures ◽  
The One

Hypertension is frequently associated with insulin resistance. We evaluated the effects of pioglitazone, an agent that increases insulin sensitivity, on the development of hypertension in the Dahl salt-sensitive (Dahl-S) rat and in the one-kidney, one-clip Sprague-Dawley rat. We also evaluated the effects of pioglitazone on growth of cultured preglomerular renal arteriolar smooth muscle cells. In Dahl-S rats fed a 3% NaCl diet, tail systolic blood pressures and direct arterial pressures were lower (P < 0.05) in pioglitazone-treated (20 mg/kg daily by gavage for 3 wk) than in control rats (n = 10 rats/group). In one-kidney, one-clip Sprague-Dawley rats, systolic blood pressures were also lower in pioglitazone-treated animals (P < 0.0001). In vitro, proliferation of arteriolar smooth muscle cells was stimulated (P < 0.01) by insulin, epidermal growth factor (EGF), and fetal calf serum (FCS); pioglitazone (5 microM) reversibly inhibited (P < 0.01) insulin-, EGF-, and FCS-induced proliferation. Pioglitazone (0.01-100 microM) also inhibited insulin- (1 mU/ml), EGF- (100 ng/ml), and 5% FCS-induced [3H]thymidine incorporation in a concentration-dependent manner (P < 0.01). Thus pioglitazone attenuated the development of hypertension in the Dahl-S rat and the one-kidney, one-clip rat. The ability of pioglitazone to inhibit growth of vascular smooth muscle may contribute to its hypotensive effect.

Interleukin-4- and -13-induced hypercontractility of human intestinal muscle cells-implication for motility changes in Crohn's disease

2005 ◽  
Vol 288 (4) ◽  
pp. G609-G615 ◽  
Author(s):  
Hirotada Akiho ◽  
Paola Lovato ◽  
Yikang Deng ◽  
Peter J. M. Ceponis ◽  
Patricia Blennerhassett ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Interleukin 4 ◽  
Stricture Formation ◽  
Cultured Smooth Muscle Cells ◽  
Muscularis Externa

Crohn's disease is an idiopathic inflammatory condition. However, little is known about the changes that occur in the muscularis externa, despite the fact that this tissue contributes to motility changes and stricture formation. We characterized immune activity in the muscularis externa from intestinal segments of Crohn's disease patients and evaluated the role of IL-4 and -13 as well as signal transducer and activator of transcription (STAT)6 in the contractility of the cultured human intestinal smooth muscle cells. CD3+ve cells ( P < 0.01) and IL-4 protein ( P < 0.01) were significantly increased in the muscularis externa of Crohn's disease patients compared with noninflamed controls. Preincubation of human cultured smooth muscle cells with IL-4 ( P < 0.001) or IL-13 ( P < 0.05) significantly enhanced carbachol-induced contraction, and this was significantly inhibited by the STAT6 inhibitor leflunomide ( P < 0.0001). A similar profile was observed in muscle cells isolated from Crohn's disease patients. Both IL-4 and IL-13 increased specific STAT6-DNA binding in control cells, and this was inhibited by anti-STAT6 Ab ( P < 0.05) or leflunomide ( P < 0.05). IL-4 and IL-13 mediate the hypercontractility of intestinal muscle via a STAT6 pathway at the level of the smooth muscle cell. The STAT6 pathway may contribute to the hypercontractility of intestinal muscle in Crohn's disease.

scholarly journals Dysfunctional vascular smooth muscle cells mediate early and late-stage neuroinflammation and Tau hyperphosphorylation

2021 ◽  
Author(s):  
Jorge A. Aguilar-Pineda ◽  
Karin J. Vera-Lopez ◽  
Pallavi Shrivastava ◽  
Rita Nieto-Montesinos ◽  
Miguel A. Chávez-Fumagalli ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Ex Vivo ◽  
Muscle Cells ◽  
Dependent Manner ◽  
Tau Hyperphosphorylation

SUMMARYDespite the emerging evidence implying early vascular contributions to neurogenerative syndromes, the role of vascular smooth muscle cells (VSMCs) in the pathogenesis of Alzheimer’s disease is still not well understood. Herein, we show that VSMCs in brains of AD patients and the animal model of the disease, are deficient in multiple VSMC-contractile markers which correlated with Tau accumulation in brain arterioles. Ex vivo and in vitro experiments demonstrated that VSMCs undergo dramatic phenotypic transitions under AD-like conditions, adopting pro-inflammatory and synthetic phenotypes. Notably, these changes coincided with Tau hyperphosphorylation at residues Y18, T205 and S262. We also observed that loss of VSMC markers occurred in an age-dependent manner, and that expression of Sm22α and α-Sma proteins were inversely correlated with CD68 and Tau accumulation in brain arterioles of 3xTg-AD mice. Together, these findings further support the contribution of VSMCs in AD pathogenesis, and nominate VSMCs as potential novel therapeutic target in AD.Graphical Abstract

scholarly journals CCN2 Increases TGF-β Receptor Type II Expression in Vascular Smooth Muscle Cells: Essential Role of CCN2 in the TGF-β Pathway Regulation

2021 ◽  
Vol 23 (1) ◽  
pp. 375
Author(s):  
Antonio Tejera-Muñoz ◽  
Laura Marquez-Exposito ◽  
Lucía Tejedor-Santamaría ◽  
Sandra Rayego-Mateos ◽  
Macarena Orejudo ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Dependent Manner ◽  
Direct Role ◽  
Pathway Activation

The cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a mediator of the fibrotic responses induced by other factors including the transforming growth factor β (TGF-β). However, several studies have defined a direct role of CCN2 acting as a growth factor inducing oxidative and proinflammatory responses. The presence of CCN2 and TGF-β together in the cellular context has been described as a requisite to induce a persistent fibrotic response, but the precise mechanisms implicated in this relation are not described yet. Considering the main role of TGF-β receptors (TβR) in the TGF-β pathway activation, our aim was to investigate the effects of CCN2 in the regulation of TβRI and TβRII levels in vascular smooth muscle cells (VSMCs). While no differences were observed in TβRI levels, an increase in TβRII expression at both gene and protein level were found 48 h after stimulation with the C-terminal fragment of CCN2 (CCN2(IV)). Cell pretreatment with a TβRI inhibitor did not modify TβRII increment induced by CCN2(VI), demonstrating a TGF-β-independent response. Secondly, CCN2(IV) rapidly activated the SMAD pathway in VSMCs, this being crucial in the upregulation of TβRII since the preincubation with an SMAD3 inhibitor prevented it. Similarly, pretreatment with the epidermal growth factor receptor (EGFR) inhibitor erlotinib abolished TβRII upregulation, indicating the participation of this receptor in the observed responses. Our findings suggest a direct role of CCN2 maintaining the TGF-β pathway activation by increasing TβRII expression in an EGFR-SMAD dependent manner activation.

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