scholarly journals Loss of Canonical Insulin Signaling Accelerates Vascular Smooth Muscle Cell Proliferation and Migration Through Changes in p27Kip1 Regulation

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 651-658 ◽  
Author(s):  
Daniel James Lightell ◽  
Stephanie Collier Moss ◽  
Thomas Cooper Woods
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Insulin Signaling ◽  
Cell Cycle Progression ◽  
Insulin Stimulation ◽  
Cycle Progression ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Proliferation And Migration

Abstract Insulin resistance is associated with an accelerated rate of atherosclerosis. Vascular smooth muscle cell (VSMC) migration and proliferation are important components of atherosclerosis. To elucidate the effects of the loss of normal insulin receptor (IR) signaling on VSMC function, we compared the proliferation and migration of murine VSMCs lacking the IR (L2-VSMCs) with wild type (WT-VSMCs). We also examined changes in the response of L2-VSMCs to insulin stimulation and to inhibition of the mammalian target of rapamycin (mTOR), a kinase critical in VSMC proliferation and migration. The L2-VSMCs exhibit greater proliferation and migration rates compared with WT-VSMCs. L2-VSMCs also exhibit a resistance to the effects of rapamycin, an mTOR inhibitor, on proliferation, migration, and cell cycle progression. The resistance to mTOR inhibition is coupled with a loss of effect on the cyclin-dependent kinase inhibitor p27Kip1, an inhibitor of cell cycle progression and VSMC migration. In response to stimulation with physiological insulin, the L2-VSMCs exhibit a loss of Akt phosphorylation and a significantly increased activation of the ERK-1/2 compared with WT-VSMCs. Insulin stimulation also decreased p27Kip1 mRNA in L2-VSMCs but not in WT-VSMCs. The effect of insulin on p27Kip1 mRNA was blocked by pretreatment with an ERK-1/2 pathway inhibitor. We conclude that loss of canonical insulin signaling results in increased ERK-1/2 activation in response to physiological insulin that decreases p27Kip1 mRNA. These data demonstrate a potential mechanism where changes in IR signaling could lead to a decrease in p27Kip1, accelerating VSMC proliferation and migration.

Circular RNA circLMF1 regulates PDGF-BB-induced proliferation and migration of human aortic smooth muscle cells by regulating the miR-125a-3p/VEGFA or FGF1 axis

2021 ◽  
pp. 1-17
Author(s):  
Yanping Yang ◽  
Wenkai Mao ◽  
Liming Wang ◽  
Lin Lu ◽  
Yunfeng Pang
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Cell Viability ◽  
Cell Cycle Progression ◽  
Muscle Cells ◽  
Cycle Progression ◽  
And Migration ◽  
Proliferation And Migration

Atherosclerosis is a major cause of cardiovascular disease, in which vascular smooth muscle cells (VSMCs) proliferation and migration play a vital role. Circular RNAs (circRNAs) have been reported to be correlated with the VSMCs function. Therefore, this study is designed to explore the role and mechanism of circRNA lipase maturation factor 1 (circLMF1) in Human aortic VSMCs (HASMCs). The microarray was used for detecting the expression of circLMF1 in proliferative and quiescent HASMCs. Levels of circLMF1, microRNA-125a-3p (miR-125a-3p), vascular endothelial growth factor A (VEGFA), and fibroblast growth factor 1 (FGF1) were determined by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, cell cycle progression, and migration were assessed by Cell Counting Kit-8 (CCK-8), flow cytometry, wound healing, and transwell assays, respectively. Western blot assay determined proliferating cell nuclear antigen (PCNA), Cyclin D1, matrix metalloproteinase (MMP2), osteopontin (OPN), VEGFA, and FGF1 protein levels. The possible interactions between miR-125a-3p and circLMF1, and miR-125a-3p and VEGFA or FGF1 were predicted by circbank or targetscan, and then verified by a dual-luciferase reporter, RNA Immunoprecipitation (RIP), RNA pull-down assays. CircLMF1, VEGFA, and FGF1 were increased, and miR-125a-3p was decreased in platelet-derived growth factor-BB (PDGF-BB)-inducted HASMCs. Functionally, circLMF1 knockdown hindered cell viability, cell cycle progression, and migration in PDGF-BB-treated HASMCs. Mechanically, circLMF1 could regulate VEGFA or FGF1 expression through sponging miR-125a-3p. Our findings revealed that circLMF1 deficiency could inhibit cell viability, cell cycle progression, and migration of PDGF-BB stimulated atherosclerosis model partly through the miR-125a-3p/VEGFA or FGF1 axis, suggesting that targeting circLMF1 can be a feasible therapeutic strategy for atherosclerosis.

Inhibitory Effects of Brazilin on the Vascular Smooth Muscle Cell Proliferation and Migration Induced by PDGF-BB

2013 ◽  
Vol 41 (06) ◽  
pp. 1283-1296 ◽  
Author(s):  
Jing Guo ◽  
Li Li ◽  
Yu-Jie Wu ◽  
Yu Yan ◽  
Xiao-Na Xu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Diseases ◽  
Inhibitory Effects ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Proliferation And Migration

Abnormal vascular smooth muscle cell (VSMC) proliferation and migration contribute to the pathogenesis of vascular diseases including atherosclerosis and restenosis. Brazilin isolated from the heartwood of Caesalpinia sappan L. has been reported to exhibit various biological activities, such as anti-platelet aggregation, anti-inflammation, vasorelaxation and pro-apoptosis. However, the functional effects of Brazilin on VSMCs remain unexplored. The present study investigated the potential effects of Brazilin on platelet-derived growth factor (PDGF)-BB induced VSMC proliferation and migration as well as the underlying mechanism of action. VSMC proliferation and migration were measured by Crystal Violet Staining, wound-healing and Boyden chamber assays, respectively. Cell cycle was analyzed by flow cytometry. Enzymatic action of matrix metalloproteinase-9 (MMP-9) was carried out by gelatin zymography. Expression of adhesion molecules, cell cycle regulatory proteins, the phosphorylated levels of PDGF receptor β (PDGF-Rβ), Src, extracellular signal regulated kinase (ERK) and Akt were tested by immunoblotting. The present study demonstrated that pretreatment with Brazilin dose-dependently inhibited PDGF-BB stimulated VSMC proliferation and migration, which were associated with a cell-cycle arrest at G0/G1 phase, a reduction in the adhesion molecule expression and MMP-9 activation in VSMCs. Furthermore, the increase in PDGF-Rβ, Src, ERK1/2 and Akt phosphorylation induced by PDGF-BB were suppressed by Brazilin. These findings indicate that Brazilin inhibits PDGF-BB induced VSMC proliferation and migration, and the inhibitory effects of Brazilin may be associated with the blockade of PDGF-Rβ - ERK1/2 and Akt signaling pathways. In conclusion, the present study implicates that Brazilin may be useful as an anti-proliferative agent for the treatment of vascular diseases.

scholarly journals Overexpressed lncRNA AC068039.4 contributes to proliferation and cell cycle progression of pulmonary artery smooth muscle cells via sponging miR-26a-5p/TRPC6 in hypoxic pulmonary arterial hypertension

2020 ◽  
Author(s):  
Yuhan Qin ◽  
Boqian Zhu ◽  
Linqing Li ◽  
Gaoliang Yan ◽  
Dong Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Artery Smooth Muscle ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background: Hypoxic pulmonary hypertension (HPH) is a devastating and incurable disease characterized by pulmonary vascular remodeling, resulting to right heart failure and even death. Accumulated evidence has confirmed long coding RNAs (lncRNAs) are involved in hypoxia induced pulmonary vascular remodeling in HPH. The exact mechanism of lncRNA in hypoxic pulmonary hypertension remains unclear. Methods：Microarray analysis was applied to investigate the profiles of lncRNA expression in pulmonary artery smooth muscle cells (PASMCs) cultured under hypoxia and normoxia condition. qRT-PCR was performed for the expression of lncRNAs, miRNA and mRNAs, western blot analysis was employed for detection the expression of proteins. CCK-8 and transwell chamber assay were applied for assessment of PASMC proliferation and migration, respectively. Besides, flow cytometry was performed for assessments of cell cycle progression. The binding between AC068039.4 and miR-26a-5p, miR-26a-5p and TRPC6 3’UTR were detected by dual luciferase reporter assay.Results：A total of 1211 lncRNAs (698 up-regulated and 513 down-regulated) were differently expressed in hypoxia induced PASMCs. Consistent with microarray analysis, quantitative PCR verified that AC068039.4 was obviously up-regulated in hypoxia induced PASMCs. Knocking down AC068039.4 alleviated proliferation and migration of PASMCs and regulated cell cycle progression through inhibiting cells entering the G0/G1 cell cycle phase. Further experiment indicated AC068039.4 promoted hypoxic PASMCs proliferation via sponging miR-26-5p. In addition, transient receptor potential canonical 6 (TRPC6) was confirmed to be a target gene of miR-26a-5p. Conclusion: In conclusion, downregulation of lncRNA AC068039.4 inhibited pulmonary vascular remodeling through AC068039.4/miR-26a-5p/TRPC6 axis, providing new therapeutic insights for the treatment of HPH.

Abstract 417: Adenosine Diphosphate Ribosyl Cyclase via PI3K-Akt and FOXO3a Up-regulating MMP-9 to Enhance Vascular Smooth Muscle Cell Proliferation and Migration in Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Yuming Li ◽  
Haitao Li ◽  
Xinfang Wang ◽  
Junya Wang ◽  
Zhongqiu Li
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Adenosine Diphosphate ◽  
High Fat ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Proliferation And Migration

The current study was designed to explore the mechanisms of vascular smooth muscle cell (VSMC) proliferation and migration induced by adenosine diphosphate ribosyl cyclase(ADPRC). In this study, 32 Male ApoE-/- mice(6 weeks old, 18-22g)on a C57BL/6J background were divided into four groups, which received normal chow (n=8, NC group), high-fat Western-type diet (n=8, 0.25% cholesterol, 21% fat,HFD group), high-fat Western-type diet,infusion of 2,2′-dihydroxyazobenzene(DHAB, a ADPRC inhibitor, 2mg/kg/day, n=8, HFD-DHAB group) intraperitoneally or high-fat Western-type diet,infusion of LY294002(a Inhibitor of Akt, 5mg/kg/d, n=8, HFD-LY group) intraperitoneally, for 10 weeks. 8 male C57BL/6J mice served as control. After 10 weeks, mice were anesthetized with chloral hydrate, aorta was removed and immediately frozen in liquid nitrogen. Aortic atherosclerotic lesions, VSMC proliferation and migration were assessed by histomorphological observation, smooth muscle actin-α(α-SMA)and proliferating cell nuclear antigen (PCNA) examination. ADPRC expression and alterations of Akt, FOXO3a, phospho-FOXO3a and MMP-9 were determined by RT-PCR, Western Blot, Immunohistochemistry or Immunofluorescence. The results showed that, in aortic atherosclerotic lesions derived from atherosclerotic mice of HFD group, an increased VSMC proliferation and migration, reflected by the up-regulation of α-SMA and PCNA expression, were observed followed by increased expression of ADPRC, Akt, FOXO3a, phospho-FOXO3a and MMP-9. The enhanced expression of ADPRC and followed alterations of FOXO3a, phospho-FOXO3a, MMP-9 as well as α-SMA, PCNA, VSMC proliferation and migration were absent in NC group and C57BL/6J control mice. Treatment with DHAB or LY294002 reversed VSMC proliferation, migration and expression of Akt, FOXO3a, phospho-FOXO3a and MMP-9 in HFD-DHAB and HFD-LY group. These data shows that high-fat Western-type diet induced ADPRC may via PI3K-Akt to phosphorylate FOXO3a up-regulating MMP-9 to enhance vascular smooth muscle cell proliferation and migration in mice.

scholarly journals Avβ3 Single-Stranded DNA Aptamer Attenuates Vascular Smooth Muscle Cell Proliferation and Migration via Ras-PI3K/MAPK Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Hong-Bing Wu ◽  
Zhi-Wei Wang ◽  
Feng Shi ◽  
Zong-Li Ren ◽  
Luo-Cheng Li ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Cell Cycle Progression ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Dna Aptamer ◽  
Mitogen Activated Protein Kinase ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Proliferation And Migration

Objectives. To observe the effect of avβ3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. Background. Percutaneous transluminal coronary angioplasty (PTCA) is currently the preferred method for the treatment of coronary heart disease. However, vascular restenosis still occurs after PTCA treatment, severely affecting the clinical efficacy of PTCA. Integrin avβ3, which is widely expressed on various cell surfaces, plays an important role in the proliferation and migration of VSMCs. Methods. In this experiment, we used systematic evolution of ligands by exponential enrichment (SELEX) to screen out avβ3 ssDNA, which has high affinity and specificity to the avβ3 protein. MTT, Transwell, and cell scratch assays were carried out to examine the effect of avβ3 ssDNA on the proliferation and migration of VSMCs. Flow cytometry was performed to detect apoptosis and cell cycle progression. The effect of avβ3 ssDNA on the Ras-phosphatidylinositol-4,5-bisphosphate 3-kinase/mitogen-activated protein kinase (PI3K/MAPK) signaling pathway was evaluated by quantitative reverse transcription polymerase chain reaction and western blot. Results. In the present study, we found that avβ3 ssDNA significantly decreased the expression of osteopontin, focal adhesion kinase, Ras, p-PI3K, and p-MAPK at both mRNA and protein levels (P<0.05). Avβ3 ssDNA also inhibited VSMC proliferation and migration while promoting apoptosis (P<0.05), as demonstrated by the upregulation of the proapoptotic proteins Bax and active caspase 3 (P<0.05). Conclusions. The findings suggest that avβ3 ssDNA inhibited the proliferation and migration of VSMCs by suppressing the activation of Ras-PI3K/MAPK signaling.

TMEM98, a novel secretory protein, promotes endothelial cell adhesion as well as vascular smooth muscle cell proliferation and migration

2020 ◽  
Author(s):  
Mei Li ◽  
Hongmei Zhu ◽  
Xiaoyan Hu ◽  
Fuhua Gao ◽  
Xinxin Hu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Endothelial Cell ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Transmembrane Protein ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Proliferation And Migration

Transmembrane protein 98 (TMEM98) is a novel gene. In a prior study, we have shown that siRNA-mediated knockdown of TMEM98 inhibited interleukin (IL)-8-promoted endothelial cell (EC) adhesion as well as vascular smooth muscle cell (VSMC) proliferation and migration in the vascular endothelial and smooth muscle cells dysfunction. Herein, we used gain- and loss-of-function approaches combined with biochemical techniques to further explore the role of TMEM98 in the vascular wall cell. The expression and secretion of TMEM98 was increased in cultured human umbilical vein endothelial cells (HUVECs) and VSMCs treated with IL-8 and platelet-derived growth factor (PDGF)-BB. Also, PDGF-BB secretion was increased in TMEM98-treated HUVECs and VSMCs. Thus, it appears that TMEM98 and PDGF-BB form a positive feedback loop in potentiation of EC adhesion as well as VSMC proliferation and migration. Knockdown of TMEM98 mediated by siRNA inhibited PDGF-BB-promoted EC adhesion by downregulating the expression of ICAM-1 and VCAM-1 as well as impaired the proliferation and migration of VSMCs through suppressing the AKT/GSK3β/cyclin D1 signaling pathway and reducing the expression of β-catenin. Hence, TMEM98 promoted EC adhesion through inducing the expression of ICAM-1/VCAM-1 and triggered VSMC proliferation and migration through activating the ERK and AKT/GSK3β signaling pathways. Taken together, TMEM98 may serve as a potential therapeutic target for the clinical treatment.

Inhibition of cell cycle progression and migration of vascular smooth muscle cells by prostaglandin D2 synthase: resistance in diabetic Goto-Kakizaki rats

2004 ◽  
Vol 287 (5) ◽  
pp. C1273-C1281 ◽  
Author(s):  
Louis Ragolia ◽  
Thomas Palaia ◽  
Tara B. Koutrouby ◽  
John K. Maesaka
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Cell Cycle Progression ◽  
Fold Increase ◽  
Wild Type ◽  
Cycle Progression ◽  
And Migration ◽  
Type 2 Diabetic

The regulation of vascular smooth muscle cell (VSMC) proliferation, migration, and apoptosis plays a clear role in the atherosclerotic process. Recently, we reported on the inhibition of the exaggerated growth phenotype of VSMCs isolated from hypertensive rats by lipocalin-type prostaglandin D2 synthase (L-PGDS). In the present study, we report the differential effects of L-PGDS on VSMC cell cycle progression, migration, and apoptosis in wild-type VSMCs vs. those from a type 2 diabetic model. In wild-type VSMCs, exogenously added L-PGDS delayed serum-induced cell cycle progression from the G1 to S phase, as determined by gene array analysis and the decreased protein expressions of cyclin-dependent kinase-2, p21Cip1, and cyclin D1. Cyclin D3 protein expression was unaffected by L-PGDS, although its gene expression was stimulated by L-PGDS in wild-type cells. In addition, platelet-derived growth factor-induced VSMC migration was inhibited by L-PGDS in wild-type cells. Type 2 diabetic VSMCs, however, were resistant to the L-PGDS effects on cell cycle progression and migration. L-PGDS did suppress the hyperproliferation of diabetic cells, albeit through a different mechanism, presumably involving the 2.5-fold increase in apoptosis and the concomitant 10-fold increase of L-PGDS uptake we observed in these cells. We propose that in wild-type VSMCs, L-PGDS retards cell cycle progression and migration, precluding hyperplasia of the tunica media, and that diabetic cells appear resistant to the inhibitory effects of L-PGDS, which consequently may help explain the increased atherosclerosis observed in diabetes.

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