Regulation of endothelin-mediated calcium mobilization in vascular smooth muscle cells by isoproterenol

1991 ◽  
Vol 260 (3) ◽  
pp. C492-C502 ◽  
Author(s):  
Y. T. Xuan ◽  
W. D. Watkins ◽  
A. R. Whorton
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Inositol Phosphates ◽  
Fold Increase ◽  
Muscle Cells ◽  
Beta Agonist ◽  
Intracellular Camp ◽  
Permeabilized Cells

We have investigated the effect of isoproterenol on endothelin-induced Ca2+ mobilization in A10 vascular smooth muscle cells. Endothelin (ET) stimulates a rapid and sustained elevation of intracellular Ca2+ mediated by production of inositol phosphates, release of intracellular Ca2+, and activation of a plasmalemmal Ca2+ influx pathway. This influx pathway appears to be a L-type channel because it is inhibited by nicardipine and activated by BAY K 8644. Depolarization of the cells, by elevating extracellular K+, activated a pharmacologically similar channel and produced a similar change in intracellular Ca2+ concentration. Preincubation of cells with isoproterenol reduced the peak Ca2+ response to endothelin and blocked the sustained elevation. However, isoproterenol did not alter K(+)-induced Ca2+ entry. Thus it appears that ET-induced entry is mediated by intracellular signals and not by depolarization. With the use of cells incubated in Ca2(+)-free medium containing 1 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, isoproterenol was shown to inhibit Ca2+ release from intracellular pools by 36 +/- 3%. Furthermore, isoproterenol pretreatment or addition of adenosine 3',5'-cyclic monophosphate (cAMP) to saponin-permeabilized cells inhibited inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]-induced Ca2+ release from intracellular sites. Similar effects were seen with forskolin. Propranolol reversed the inhibitory effects of isoproterenol. Isoproterenol pretreatment also inhibited the rapid formation of Ins(1,4,5)P3 and [2-3H]inositol 1,3,4,5-tetrakisphosphate stimulated by endothelin and reduced the sustained formation of these compounds. Finally, isoproterenol and forskolin led to a greater than 10-fold increase in intracellular cAMP levels. This stimulation of adenylate cyclase by isoproterenol was completely blocked by propranolol. It appears then that the beta-agonist isoproterenol interacts with a beta-adrenergic receptor, elevates cAMP, and thereby alters endothelin-induced Ca2+ mobilization. Inhibition of Ins(1,4,5)P3 formation, reduction in the responsiveness of the Ins(1,4,5)P3 intracellular receptor, and perhaps inhibition of ET-induced Ca2+ entry appear to be involved.

Thapsigargin stimulates Ca2+ entry in vascular smooth muscle cells: nicardipine-sensitive and -insensitive pathways

1992 ◽  
Vol 262 (5) ◽  
pp. C1258-C1265 ◽  
Author(s):  
Y. T. Xuan ◽  
O. L. Wang ◽  
A. R. Whorton
Keyword(s):  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Inositol Polyphosphate ◽  
Inositol Polyphosphates ◽  
Permeabilized Cells ◽  
Inositol 1,4,5 Trisphosphate

We have investigated the role of the sarcoplasmic reticulum Ca2+ pool in regulating Ca2+ entry in vascular smooth muscle cells using a receptor-independent means of mobilizing the intracellular Ca2+ pool. Thapsigargin (TG) has been shown to inhibit the endoplasmic reticulum Ca(2+)-ATPase, mobilize intracellular Ca2+, and activate Ca2+ entry in nonmuscle tissues. When smooth muscle cells were treated with 0.2 microM TG, cytosolic Ca2+ concentrations rose gradually over 8 min to a peak value of 365 +/- 18 nM. Cytosolic Ca2+ remained elevated for at least 20 min and was supported by continued entry of extracellular Ca2+. TG also stimulated entry of Mn2+ and 45Ca2+ from outside the cell. Importantly, TG-induced Ca2+ entry and Mn2+ entry were found to occur through mechanisms that were independent of L-type Ca2+ channel activation because influx was not inhibited by concentrations of nicardipine that were found to block either endothelin- or 100 mM extracellular K(+)-induced cation influx. The mechanism through which TG activates cation entry appears to involve mobilization of the inositol 1,4,5-trisphosphate-responsive intracellular Ca2+ pool. In permeabilized cells, TG prevented ATP-stimulated Ca2+ uptake into the sarcoplasmic reticulum and slowly released sequestered Ca2+. The Ca2+ pool involved was responsive to inositol 1,4,5-trisphosphate. However, TG did not initiate the formation of inositol polyphosphates. Thus TG mobilizes the sarcoplasmic reticulum Ca2+ pool and activates Ca2+ entry through a nicardipine-insensitive Ca2+ channel in vascular smooth muscle. The mechanism is independent of inositol polyphosphate formation.

scholarly journals Glucocorticoids stimulate collagen and noncollagen protein synthesis in cultured vascular smooth muscle cells.

1984 ◽  
Vol 98 (2) ◽  
pp. 541-549 ◽  
Author(s):  
D C Leitman ◽  
S C Benson ◽  
L K Johnson
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Specific Activity ◽  
Fold Increase ◽  
Muscle Cells ◽  
Type I ◽  
Twofold Increase ◽  
In Cells

The effect of glucocorticoids on collagen synthesis was examined in cultured bovine aortic smooth muscle (BASM) cells. BASM cells treated with 0.1 microM dexamethasone during their proliferative phase (11 d) were labeled with [3H]proline for 24 h, and the acid-precipitable material was incubated with bacterial collagenase. Dexamethasone produced an approximate twofold increase in the incorporation of proline into collagenase-digestible protein (CDP) and noncollagen protein (NCP) in the cell layer and medium. The stimulation was present in both primary mass cultures and cloned BASM. An increase in CDP and NCP was detected at 0.1 nM, while maximal stimulation occurred at 0.1 microM. Only cells exposed to dexamethasone during their log phase of growth (1-6 d after plating) showed the increase in CDP and NCP when labeled 11 d after plating. The stimulatory effect was observed in BASM cells treated with the natural bovine glucocorticoid, cortisol, dexamethasone, and testosterone, but was absent in cells treated with aldosterone, corticosterone, cholesterol, 17 beta-estradiol, and progesterone. The increase in CDP and NCP was absent in cells treated with the inactive glucocorticoid, epicortisol, and totally abolished by the antagonist, 17 alpha-hydroxyprogesterone, suggesting that the response was mediated by specific cytoplasmic glucocorticoid receptors. Dexamethasone-treated BASM cells showed a 4.5-fold increase in the specific activity of intracellular proline, which was the result of a twofold increase in the uptake of proline and depletion of the total proline pool. After normalizing for specific activity, dexamethasone produced a 2.4- and 2.8-fold increase in the rate of collagen and NCP synthesis, respectively. Cells treated with dexamethasone secreted 1.7-fold more collagen protein in 24 h compared to control cultures. The BASM cells secreted 70% Type I and 30% Type III collagen into the media as assessed by two-dimensional gel electrophoresis. The ratio of these two types was not altered by dexamethasone. The results of the present study demonstrate that glucocorticoids can act directly on vascular smooth muscle cells to increase the synthesis and secretion of collagen and NCP.

Platelet inhibition by an L-arginine-derived substance released by IL-1 beta-treated vascular smooth muscle cells

1991 ◽  
Vol 261 (6) ◽  
pp. H2024-H2030
Author(s):  
W. Durante ◽  
V. B. Schini ◽  
T. Scott-Burden ◽  
D. C. Junquero ◽  
M. H. Kroll ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Smooth Muscle ◽  
Platelet Aggregation ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Fold Increase ◽  
Muscle Cells ◽  
Platelet Inhibition ◽  
Nitrite Production

Experiments were performed to examine whether stimulation of cultured vascular smooth muscle cells by interleukin (IL)-1 beta would induce platelet inhibitory properties of these cells. Incubation of platelets with untreated rat aortic smooth muscle cells had no effect on thrombin-induced platelet aggregation. In contrast, incubation of platelets with IL-1 beta-pretreated smooth muscle cells or the perfusate from such cells resulted in the inhibition of thrombin-induced platelet aggregation. This effect was potentiated by superoxide dismutase and reversed by incubating the IL-1 beta-treated smooth muscle cells with NG-nitro-L-arginine (L-NNA) or by treating the platelets with methylene blue. Cytokine-treated smooth muscle cells inhibited thrombin-stimulated changes in platelet cytosolic ionized calcium, whereas untreated cells were without effect. Incubating platelets with IL-1 beta-treated smooth muscle cells resulted in a 10-fold increase in platelet guanosine 3',5'-cyclic monophosphate (cGMP) levels, whereas untreated smooth muscle cells had no effect. The elevation of platelet cGMP induced by the IL-1 beta-treated smooth muscle cells was prevented by exposing the cytokine-treated cells to L-NNA or by treating platelets with methylene blue. Treatment of smooth muscle cells with IL-1 beta also resulted in an eightfold increase in nitrite production, which was blocked when the cells were incubated with L-NNA. The addition of cycloheximide to smooth muscle cells during their incubation with IL-1 beta completely inhibited smooth muscle cell nitrite production, the effects of the smooth muscle cells on platelet cGMP levels, and platelet responses to thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Rapid desensitization of vasopressin-stimulated phosphatidylinositol 4,5-bisphosphate and phosphatidylcholine hydrolysis questions the role of these pathways in sustained diacylglycerol formation in A10 vascular-smooth-muscle cells

1992 ◽  
Vol 285 (3) ◽  
pp. 759-766 ◽  
Author(s):  
R Plevin ◽  
M J O Wakelam
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Receptor Antagonist ◽  
Vascular Smooth Muscle Cells ◽  
Inositol Phosphates ◽  
Muscle Cells ◽  
Receptor Activation ◽  
V1a Receptor ◽  
In Cells

The kinetics of vasopressin-stimulated PtdIns(4,5)P2 and phosphatidylcholine (PtdCho) hydrolysis in relation to sustained diacylglycerol (DAG) formation was investigated in A10 vascular-smooth-muscle cells in culture. Vasopressin stimulated a transient increase in Ins(1,4,5)P3 mass formation, which was mirrored by a decrease in PtdIns(4,5)P2 mass levels. Vasopressin stimulated sustained accumulation of total [3H]inositol phosphates ([3H]IP) in the presence of Li+; however, this was significantly decreased by adding a vasopressin-receptor antagonist at different times after initial stimulation. Vasopressin-stimulated phospholipase D (PLD) activity was found to be a transient phenomenon lasting approx. 2 min. Experiments involving agonist preincubation with subsequent addition of butanol confirmed that vasopressin-stimulated PLD activity was desensitized. Vasopressin stimulated an increase in formation of choline, but not of phosphocholine, suggesting that PLD was the major catalytic route of PtdCho hydrolysis in this cell line. The roles of choline and inositol phospholipid hydrolysis in the prolonged phase of DAG formation was examined by comparing vasopressin-stimulated changes in DAG levels in the presence of butanol, the protein kinase C inhibitor Ro-31-8220 or a V1a-receptor antagonist. Vasopressin-stimulated DAG formation was decreased by 40-50% in the presence of butanol between 1 and 10 min; however, during more prolonged stimulation butanol was without significant effect. In cells pretreated with Ro-31-8220, vasopressin-stimulated DAG formation was decreased by approx. 30% at 2 min, but was significantly potentiated at later times. This coincided with an enhancement of vasopressin-stimulated [3H]IP accumulation. In cells exposed to the V1a-receptor antagonist 5 min after addition of vasopressin, subsequent DAG formation was significantly decreased, indicating that sustained formation of DAG, like [3H]IP accumulation, was dependent on continual agonist receptor activation. The results are discussed in terms of different phospholipid-hydrolytic pathways providing DAG generation.

scholarly journals Heparin regulates the collagen phenotype of vascular smooth muscle cells: induced synthesis of an Mr 60,000 collagen.

1985 ◽  
Vol 100 (2) ◽  
pp. 613-619 ◽  
Author(s):  
R A Majack ◽  
P Bornstein
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Dermatan Sulfate ◽  
Fold Increase ◽  
Muscle Cells ◽  
Maximal Effect ◽  
Early Passage

The effect of heparin on the biosynthetic phenotype of rat vascular smooth muscle cells (SMC) was investigated in vitro. Addition of heparin to the culture medium of early passage rat SMC resulted in a marked (3-15-fold) increase of a cell layer-associated Mr 60,000 protein that was sensitive to digestion by purified bacterial collagenase and contained significant amounts of hydroxyproline. Pulse-chase analysis of heparin-treated SMC revealed that the Mr 60,000 collagen was a primary and abundant product of these cells and was not processed extracellularly to a smaller form. The inductive effect of heparin could be mimicked by iota carrageenan or dextran sulfates but not by hyaluronic acid, dermatan sulfate, or chondroitin sulfates. The induction was concentration dependent with a maximal effect observed at a heparin concentration of 10 micrograms/ml. Synthesis of the Mr 60,000 collagen increased 18-24 h after addition of heparin to the cultures. Following induction and subsequent removal of heparin, synthesis of the protein remained maximal for at least 12 h and required 72 h to return to a basal level. These data demonstrate that the biosynthetic phenotype of vascular SMC in vitro can be controlled, at least in part, by heparin and related polyanions and suggest a role for similar molecules endogenous to the vessel wall in the regulation of SMC function.

Inhibitory Effects of Propofol on Intracellular Signaling by Endothelin-1 in Aortic Smooth Muscle Cells 

1998 ◽  
Vol 88 (2) ◽  
pp. 452-460 ◽  
Author(s):  
Kumiko Tanabe ◽  
Osamu Kozawa ◽  
Takehiro Kaida ◽  
Hiroyuki Matsuno ◽  
Masayuki Niwa ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Intracellular Signaling ◽  
Inositol Phosphates ◽  
Muscle Cells ◽  
Aortic Smooth Muscle ◽  
Endothelin 1 ◽  
Gtp Binding

Background Blood pressure decreases when propofol is administered. However, the exact mechanism underlying the vascular effects of propofol has not yet been elucidated. Endothelin produced by vascular endothelial cells is a potent vasoactive peptide that elicits prolonged contraction of vascular smooth muscle cells. The effects of propofol on endothelin-1-induced intracellular signaling in an aortic smooth muscle cell line, A10 cells, were examined. Methods Cultured A10 cells were pretreated with propofol for 20 min and then stimulated with endothelin-1. The effect of propofol on the endothelin-1-induced Ca2+ influx into A10 cells was evaluated by measuring intracellular 45Ca2+. The effects of propofol on the endothelin-1-induced activation of phosphatidylinositol-hydrolyzing phospholipase C and phosphatidylcholine-hydrolyzing phospholipase D were evaluated by measuring the formation of inositol phosphates and choline, respectively. The effect of propofol on endothelin-1 binding to its receptor was determined by an [125I] endothelin-1-binding assay. Results Propofol inhibited the endothelin-1-induced Ca2+ influx, but this was significant only at supuraclinical concentrations. The endothelin-1-stimulated formation of inositol phosphates was significantly suppressed by propofol. However, propofol had no effect on the formation of inositol phosphates induced by NaF, an activator of heterotrimeric guanosine triphosphate (GTP)-binding proteins. Propofol inhibited the endothelin-1-induced formation of choline. Propofol had no effect on the binding of endothelin-1 to its receptor. Conclusions These results suggest that propofol inhibits endothelin-1-induced intracellular signaling in vascular smooth muscle cells. The inhibitory effect of propofol might be exerted at a point between the endothelin-1 receptor and its GTP-binding protein. However, because all significant effects are observed at high concentrations, clinical relevance is unclear.

scholarly journals Aldosterone Enhances IGF-I-Mediated Signaling and Biological Function in Vascular Smooth Muscle Cells

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5851-5864 ◽  
Author(s):  
Teresa Cascella ◽  
Yashwanth Radhakrishnan ◽  
Laura A. Maile ◽  
Walker H. Busby ◽  
Katherine Gollahon ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Synergistic Effects ◽  
Fold Increase ◽  
Muscle Cells ◽  
Αvβ3 Integrin ◽  
Vsmc Proliferation ◽  
Igf I

The IGF-I pathway and renin-angiotensin-aldosterone axis are both involved in the pathogenesis of hypertension and atherosclerosis, but no information is available about IGF-I and aldosterone interaction or their potential synergistic effects in vascular smooth muscle cells (VSMCs). The aims of this study were to investigate whether aldosterone influences IGF-I signaling and to determine the mechanism(s) by which aldosterone affects IGF-I function. Aldosterone resulted in significant increases in the Akt (1.87 ± 0.24, P < 0.001), MAPK (1.78 ± 0.13, P < 0.001), p70S6kinase (1.92 ± 0.15, P < 0.001), IGF-I receptor (1.69 ± 0.05, P < 0.01), and insulin receptor substrate-1 (1.7 ± 0.04, P < 0.01) (fold increase, mean ± SEM, n = 3) phosphorylation responses to IGF-I compared with IGF-I treatment alone. There were also significant increases in VSMC proliferation, migration, and protein synthesis (1.63 ± 0.03-, 1.56 ± 0.08-, and 1.51 ± 0.04-fold increases compared with IGF-I alone, respectively, n = 3, P < 0.001). Aldosterone induced osteopontin (OPN) mRNA expression and activation of αVβ3-integrin as well as an increase in the synthesis of IGF-I receptor. The enhancing effects of aldosterone were inhibited by eplerenone (10 μmol/liter), actinomycin-D (20 nmol/liter), and an anti-αVβ3-integrin antibody that blocks OPN binding. The antioxidant N-acetylcysteine (2 mmol/liter) completely inhibited the ability of aldosterone to induce any of these changes. In conclusion, our results show that aldosterone enhances IGF-I signaling and biological actions in VSMCs through induction of OPN followed by its subsequent activation of the αVβ3-integrin and by increasing IGF-I receptor. These changes are mediated in part through increased oxidative stress. The findings suggest a new mechanism by which aldosterone could accelerate the development of atherosclerosis.

scholarly journals Desensitisation of calcitonin gene-related peptide responsiveness but not adrenomedullin responsiveness in vascular smooth muscle cells

2000 ◽  
Vol 165 (1) ◽  
pp. 133-138 ◽  
Author(s):  
WM Drake ◽  
SR Lowe ◽  
A Mirtella ◽  
TJ Bartlett ◽  
AJ Clark
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Calcitonin Gene Related Peptide ◽  
Intracellular Camp ◽  
Related Peptide ◽  
Calcitonin Gene

Adrenomedullin (ADM) and calcitonin gene-related peptide (CGRP) are distantly related peptides. Both act through G protein-coupled receptors on vascular smooth muscle cells to increase intracellular cAMP concentrations, causing vasorelaxation. Recent evidence suggests that both peptides bind to a common heptahelical receptor, with specificity for each peptide being determined by a receptor activity modifying protein (RAMP). This hypothesis predicts that each peptide should desensitise the cellular response to subsequent stimulation by the other. We have studied the patterns of desensitisation of ADM/CGRP receptors in rat aortic vascular smooth muscle cells. Cells were incubated for 20 min in either serum free medium (SFM), alone (control) or in SFM containing vasoactive agonist (e.g. ADM 10(-8) M, CGRP 10(-7) M, angiotensin II 10(-9) M or isoproterenol 10(-6) M). Cells were then washed and incubated for a further 20 min in SFM containing a second agonist and 1 mM isobutyryl methyl xanthine. Cells were harvested and assayed for cAMP. Pre-exposure of cells to CGRP, isoproterenol, angiotensin II or ADM, decreased cAMP generation in response to subsequent stimulation with CGRP by 84% (+/-5), 66% (+/-18), 45% (+/-5) and 60% (+/-10) respectively (mean+/-s.d.). Pre-incubation of cells with 100 nM H-89, a protein kinase A (PKA) inhibitor, abolished the desensitisation of CGRP by itself, implying that this desensitisation was mediated through PKA. In contrast, there was no attenuation of the cAMP response to stimulation with ADM by pre-exposure to ADM and all other agonists tested. Identical results were seen with or without PKA inhibition by H-89. These results indicate that the ADM receptor does not desensitise over this time period in RAVSMCs, in contrast to the CGRP receptor, which is desensitised by pre-exposure to CGRP and other vaso-active agonists. These data also suggest that ADM and CGRP act through separate receptors in these cells.

Abstract P292: ENPP1-Fc Protein Inhibits Proliferation of Human Vascular Smooth Muscle Cells

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Yan Yan ◽  
Anumeha Shah ◽  
Ashmita Saigal ◽  
Susan Faas ◽  
Zhiliang Cheng ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Cellular Proliferation ◽  
Fold Increase ◽  
Muscle Cells ◽  
Arterial Stenosis ◽  
Arterial Calcification ◽  
Inorganic Pyrophosphate

Background: Arterial stenosis leading to hypertension or heart failure is common in patients with Generalized Arterial Calcification of Infancy (GACI), an ultra-rare disease associated with loss of function mutations in ENPP1, an ectonucleotide pyrophosphatase that hydrolyzes extracellular ATP. GACI is characterized by accelerated calcification and severe myointimal proliferation. The role of ENPP1 in myoinitimal proliferation is unknown. Here, we examined the effect of ENPP1 on proliferation of human vascular smooth muscle cells (hVSMCs). Methods: ENPP1 expression was assessed in primary hVSMCs using qRT-PCR. ENPP1 expression was silenced using siRNA and its activity was verified by a cell based assay or inorganic pyrophosphate (PPi) assay and its effect on VSMC proliferation was determined by 3H-thymidine incorporation. Results: Treatment of primary hVSMCs with siRNA specific to the hENPP1 resulted in ~90% decrease in ENPP1 levels. Cellular enzyme activity correlated with ENPP1 expression in VSMCs. Silencing ENPP1 in hVSMCs led to 1-3 fold increase in proliferation relative to that of cells transfected with control siRNA in 2 out of 2 donors. Peak cell proliferation was observed at 5 days post-transfection. Human iPSC derived VSMCs (iVSMCs) expressed higher levels of ENPP1 than primary hVSMCs. Silencing ENPP1 in iVSMCs resulted in 3-5 fold increase in proliferation relative to that of cells transfected with negative control siRNA in 2 out of 2 donors. Addition of recombinant ENPP1-Fc protein restored ENPP1- associated proliferation in all donors (8099.75 ±134.32 (untreated) vs 1478 ± 55.34 (5ug/ml ENPP1-Fc treated, P<0.001)). In contrast, bisphosphonates, a current off-label treatment for patients with GACI, had no effect on cellular proliferation. Increased levels of PPi were also detected in culture supernatants obtained from cells treated with the ENPP1-Fc protein. Conclusion: For the first time, we have demonstrated that ENPP1 knockdown promotes proliferation of human VSMCs, and treatment with a functionally active ENPP1-Fc protein significantly inhibits ENPP1-associated proliferation. These results suggest that ENPP1 enzyme replacement may be a potential strategy to treat myointimal proliferation in patients with GACI disease.

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