Abstract 210: Milk Fat Globule Epidermal Growth Factor VIII Mediates Vascular Remodeling by Increasing Inflammation and Smooth Muscle Activation

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Ting-Hein Lee ◽  
Shigekazu Nagata ◽  
Kamran Atabai ◽  
Hou-Yu Chiang
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Vascular Remodeling ◽  
Milk Fat ◽  
Vessel Wall ◽  
Inflammatory Cell ◽  
Neointimal Formation ◽  
Vsmc Proliferation ◽  
Milk Fat Globule ◽  
And Migration

Vascular remodeling, defined as a change in the geometry of the vessel wall, occurs in the pathological process of vascular diseases, like atherosclerosis, hypertension and restenosis. The resulting neointimal formation is a part of a reparative response including thrombosis, inflammatory cell infiltration, vascular smooth muscle cell (VSMC) proliferation and migration, which lead to the stenosis of blood vessels and the restricted blood flow. Milk fat globule epidermal growth factor VIII (Mfge8), a secreted glycoprotein, is well-characterized for its capacity of assisting the clearance of apoptotic cells in vascular system. Recently, Mfge8 has been identified as a pivot relay between pro-inflammatory signals and activated VSMCs, contributing to intima-media thickening of the vessel wall by promoting VSMC proliferation and migration in aged arteries. We have noted intense Mfge8 expression in the endothelial cells and VSMCs of the carotid artery following ligation injury in mice, suggesting that Mfge8 may regulate the two characteristics of vascular remodeling, inflammatory cell infiltration and VSMC activation, in response to low blood flow. To elucidate the functions of Mfge8 in a flow-induced model of vascular remodeling, a complete carotid ligation was conducted in wild-type (WT) or Mfge8 knockout (KO) mice. Morphometric analysis demonstrated that genetic deletion of Mfge8 in mice reduces carotid intima and media thickening compared to WT mice. Deficiency of Mfge8 prevented VSMC phenotypic modulation, as evidenced by the decreased expression of smooth muscle myosin heavy chain and attenuated cell proliferation in tunica media after ligation injury. VSMCs transfected with SiRNA against Mfge8 migrated slower than in controls as early as 0.5 days post-platelet-derived growth factor (PDGF) stimulation. Further, Mfge8-null mice showed a dramatic decrease in leukocyte infiltration into the vessel wall. Collectively, in a flow-induced model of vascular remodeling, Mfge8 plays a crucial role in VSMC migration and proliferation, as well as inflammatory cell accumulation, thereby regulating neointimal formation.

Abstract 512: Collagen Homologous Sequence R1R2 Mediates Vascular Remodeling by Decreasing Inflammation and Smooth Muscle Proliferation

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Ting-Hein Lee ◽  
Hou-Yu Chiang
Keyword(s):  
Smooth Muscle ◽  
Vascular Disease ◽  
Vascular Remodeling ◽  
Vessel Wall ◽  
Inflammatory Cell ◽  
Vascular Diseases ◽  
Inflammatory Cell Infiltration ◽  
Collagen I ◽  
Cell Infiltration ◽  
Ecm Proteins

The extracellular matrix (ECM) is a major constituent of the vessel wall. Except for providing a structural scaffold for cells, ECM controls numerous cellular functions like adhesion, growth, migration and differentiation. The components of ECM are mediated by the interplay between ECM synthesis, deposition, degradation and the interaction between ECM proteins. Vascular remodeling occurs in the vascular diseases and is characterized by endothelial cell activation, inflammatory cell infiltration, smooth muscle cell (SMC) proliferation/migration, and augmented deposition of ECM proteins. Collagen I is the major ECM component in the arterial wall, excess collagen I accumulation may exacerbate the vascular disease by further facilitating SMC proliferation/migration. Therefore, treatments to inhibit excess collagen deposition could provide a remedy for vascular disease. R1R2, a peptide derived from the bacterial adhesin SFS with sequence homology to collagen, is known to inhibit collagen I deposition by inhibiting the binding of fibronectin to collagen. Studies have revealed that R1R2 affects collagen I-dependent cell growth and migration in vitro. However, the in vivo functions of R1R2 during vascular remodeling remain unknown. We hypothesized that R1R2 prevents excess collagen I accumulation and SMC proliferation, resulting in decreased neointimal formation. We induced vascular remodeling by ligating the carotid artery on mice. Delivery of R1R2 was periadventially applied using pluronic gel and evaluated its effects on vascular remodeling, ECM deposition, SMC proliferation and differentiation. Morphometric analysis demonstrated that R1R2 reduced intima-media thickening by 50% compared to the control group. R1R2 treatment also decreased collagen I deposition in the vessel wall and maintained SMC in the contractile phenotype. Interestingly, R1R2 dramatically reduced inflammatory cell infiltration into the vessel by 80% accompanied with decreased VCAM-1 and ICAM-1. In conclusion, our data showed that R1R2 attenuates the vascular remodeling response by decreasing inflammation and SMC proliferation/migration. These studies provide a therapeutic potential of periadventitially delivering R1R2 in treating vascular diseases.

Abstract 15691: The Novel High Mobility Group Protein Hmgxb4 Promotes Neointimal Formation in Response to Arterial Injury

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
xiangqin he ◽  
Kunzhe Dong ◽  
Jian Shen ◽  
Islam Osman ◽  
Guoqing Hu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Neointimal Hyperplasia ◽  
Critical Role ◽  
High Mobility ◽  
Arterial Injury ◽  
The Novel ◽  
Neointimal Formation ◽  
Vsmc Proliferation ◽  
And Migration

Introduction: Restenosis after percutaneous intervention is predominantly attributed to proliferation and migration of vascular smooth muscle cells (VSMCs). However, the key regulators responsible for VSMC proliferation and migration remain to be identified. Hypothesis: We previously reported that the novel high mobility group (HMG) nuclear protein HMGXB4 (HMG-Box containing 4) plays a critical role in the de-differentiation of vascular smooth muscle cells in vitro and in acute inflammatory response to septic shock. We hypothesize that HMGXB4 is critical for neointimal hyperplasia in response to inflammatory stimuli. Methods and Results: We found that the expression of HMGXB4 is dramatically induced in ligation or wire injury-induced neointimal hyperplasia and correlated with the activation of inflammatory signaling in mice. Using an inducible smooth muscle-specific Hmgxb4 KO (knockout) mice model, we found specific KO of Hmgxb4 in VSMCs ameliorates ligation- or wire- injury induced neointimal formation. Among an array of growth factors and inflammation cytokines, we found that TNFα and INFγ effectively induces the expression of HMGXB4 in VSMCs and correlates with the VSMC proliferation in vitro. Furthermore, we found deletion of HMGXB4 attenuates while over-expression of HMGXB4 promotes inflammation cytokines-induced VSMC proliferation in vitro. These results suggest injury-induced inflammatory signal triggers HMGXB4 induction, which, in turn, promotes the VSMC proliferation and neointimal formation. Conclusions: Our study not only demonstrates a critical role of HMGXB4 in promoting neointimal hyperplasia in response the arterial injury, but also suggests HMGXB4 is a potential novel target for the management of restenosis in human.

Signal transduction of betacellulin in growth and migration of vascular smooth muscle cells

2004 ◽  
Vol 287 (3) ◽  
pp. C807-C813 ◽  
Author(s):  
Mizuo Mifune ◽  
Haruhiko Ohtsu ◽  
Hiroyuki Suzuki ◽  
Gerald D. Frank ◽  
Tadashi Inagami ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Muscle Cells ◽  
Egf Family ◽  
And Migration

Epidermal growth factor (EGF) family ligands have been implicated in cardiovascular diseases because of their enhanced expression in vascular lesions and their promoting effects on growth and migration of vascular smooth muscle cells (VSMCs). Betacellulin (BTC), a novel EGF family ligand, has been shown to be expressed in atherosclerotic lesions and to be a potent growth factor of VSMCs. However, the molecular mechanisms downstream of BTC involved in mediating vascular remodeling remain largely unknown. Therefore, the aim of this study was to examine the effects of BTC on signal transduction, growth, and migration in VSMCs. We found that BTC stimulated phosphorylation of EGF receptor (EGFR) at Tyr1068, which was completely blocked by an EGFR kinase inhibitor, AG-1478. BTC also phosphorylated ErbB2 at Tyr877, Tyr1112, and Tyr1248 and induced association of ErbB2 with EGFR, suggesting their heterodimerization in VSMCs. In postreceptor signal transduction, BTC stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and p38 mitogen-activated protein kinase (MAPK). Moreover, BTC stimulated proliferation and migration of VSMCs. ERK and Akt inhibitors suppressed migration markedly and proliferation partially, whereas the p38 inhibitor suppressed migration partially but not proliferation. In addition, we found the presence of endogenous BTC in conditioned medium of VSMCs and an increase of BTC on angiotensin II stimulation. In summary, BTC promotes growth and migration of VSMCs through activation of EGFR, ErbB2, and downstream serine/threonine kinases. Together with the expression and processing of endogenous BTC in VSMCs, our results suggest a critical involvement of BTC in vascular remodeling.

scholarly journals H3K4 Methyltransferase Smyd3 Mediates Vascular Smooth Muscle Cell Proliferation, Migration, and Neointima Formation

2021 ◽  
Author(s):  
Di Yang ◽  
Zhenghua Su ◽  
Gang Wei ◽  
Fen Long ◽  
Yichun Zhu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Neointimal Hyperplasia ◽  
Neointima Formation ◽  
Balloon Injury ◽  
Neointimal Formation ◽  
And Migration ◽  
Proliferation And Migration

Objective: Smyd3 (SET and MYND domain-containing protein 3) is an H3K4 (histone H3 lysine 4) dimethyltransferase and trimethyltransferase that activates the transcription of oncogenes and cell cycle genes in human cancer cells. We discovered its overexpression in proliferative vascular smooth muscle cells (VSMCs). However, whether Smyd3 plays a role in vascular remodeling remains unanswered. The objective of this study is to investigate the role and underlying mechanism of Smyd3 in phenotypic transition of VSMCs (such as proliferation and migration) and vascular remodeling (such as neointima formation). Approach and Results: We discovered upregulation of Smyd3 in both PDGF (platelet-derived growth factor) BB–induced vascular cell proliferation model and balloon injury–induced neointima formation model. Knockdown of Smyd3 or blockade of its enzymatic activity suppressed VSMCs proliferation and migration ability, whereas Smyd3 overexpression promoted VSMC migration and proliferation. Mechanistically, RNA-seq and ChIP-seq analysis revealed Smyd3 promoted neointimal formation by directly binding and increasing H3K4me3 to the promoter regions of target genes that are associated with cell proliferation and migration, cell cycle control. Furthermore, knockout of Smyd3 in mice profoundly suppressed carotid artery ligation–induced neointimal hyperplasia, consistently, local knocking down Smyd3 in rats relieved balloon injury–induced neointimal formation, while restored VSMC contractile protein expression, suggesting that Smyd3 plays a critical role in vivo. Conclusions: Our results demonstrate that Smyd3 promotes VSMC proliferation and migration during injury-induced vascular remodeling, which provide a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.

scholarly journals Lentiviral-Mediated shRNA Silencing of PDE4D Gene Inhibits Platelet-Derived Growth Factor-Induced Proliferation and Migration of Rat Aortic Smooth Muscle Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Lin Liu ◽  
Xiaowei Xu ◽  
Jiejie Li ◽  
Xia Li ◽  
Wenli Sheng
Keyword(s):  
Smooth Muscle ◽  
Ischemic Stroke ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Platelet Derived Growth Factor ◽  
Intracellular Camp ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Proliferation And Migration

Phosphodiesterase 4D (PDE4D) is a member of the large superfamily of phosphodiesterases. PDE4D polymorphisms have been found to associate with ischemic stroke. Proliferation and migration of vascular smooth muscle cells (VSMCs) play a critical role in the pathogenesis of atherosclerosis. In this study, infection of VSMCs with lentivrius particles carrying shRNA direct against PDE4D significantly inhibited platelet-derived growth factor-induced VSMC proliferation and migration, and the inhibitory effects were not associated with global intracellular cAMP level. Our results implicate that PDE4D has an important role in VSMC proliferation and migration which may explain its genetic susceptibility to ischemic stroke.

Endogenous VEGF-A is responsible for mitogenic effects of MCP-1 on vascular smooth muscle cells

2004 ◽  
Vol 286 (5) ◽  
pp. H1978-H1984 ◽  
Author(s):  
Astrid Parenti ◽  
Lydia Bellik ◽  
Laura Brogelli ◽  
Sandra Filippi ◽  
Fabrizio Ledda
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Vsmc Proliferation ◽  
Low Concentrations ◽  
Receptor Upregulation ◽  
And Migration ◽  
Proliferation And Migration

Vessel wall remodeling is a complex phenomenon in which the loss of differentiation of vascular smooth muscle cells (VSMCs) occurs. We investigated the role of rat macrophage chemoattractant protein (MCP)-1 on rat VSMC proliferation and migration to identify the mechanism(s) involved in this kind of activity. Exposure to very low concentrations (1–100 pg/ml) of rat MCP-1 induced a significant proliferation of cultured rat VSMCs assessed as cell duplication by the counting of total cells after exposure to test substances. MCP-1 stimulated VSMC proliferation and migration in a two-dimensional lateral sheet migration of adherent cells in culture. Endogenous vascular endothelial growth factor-A (VEGF-A) was responsible for the mitogenic activity of MCP-1, because neutralizing anti-VEGF-A antibody inhibited cell proliferation in response to MCP-1. On the contrary, neutralizing anti-fibroblast growth factor-2 and anti-platelet-derived growth factor-bb antibodies did not affect VSMC proliferation induced by MCP-1. RT-PCR and Western blot analyses showed an increased expression of either mRNA or VEGF-A protein after MCP-1 activation (10–100 pg/ml), whereas no fms-like tyrosine kinase (Flt)-1 receptor upregulation was observed. Because we have previously demonstrated that hypoxia (3% O2) can enhance VSMC proliferation induced by VEGF-A through Flt-1 receptor upregulation, the effects of hypoxia on the response of VSMCs to MCP-1 were investigated. Severe hypoxia (3% O2) potentiated the growth-promoting effect of MCP-1, which was able to significantly induce cell proliferation even at a concentration as low as 0.1 pg/ml. These findings demonstrate that low concentrations of rat MCP-1 can directly promote rat VSMC proliferation and migration through the autocrine production of VEGF-A.

scholarly journals MIA SH3 Domain ER Export Factor 3 Deficiency Prevents Neointimal Formation by Restoring BAT-Like PVAT and Decreasing VSMC Proliferation and Migration

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu Lei ◽  
Jianfei Xu ◽  
Mengju Li ◽  
Ting Meng ◽  
Meihua Chen ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Association Studies ◽  
Neointimal Hyperplasia ◽  
Vascular Diseases ◽  
Genome Wide Association Studies ◽  
Neointimal Formation ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Er Export ◽  
Proliferation And Migration

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) and excessive accumulation of dysfunctional PVAT are hallmarks of pathogenesis after angioplasty. Recent genome-wide association studies reveal that single-nucleotide polymorphism (SNP) in MIA3 is associated with atherosclerosis-relevant VSMC phenotypes. However, the role of MIA3 in the vascular remodeling response to injury remains unknown. Here, we found that expression of MIA3 is increased in proliferative VSMCs and knockdown of MIA3 reduces VSMCs proliferation, migration, and inflammation, whereas MIA3 overexpression promoted VSMC migration and proliferation. Moreover, knockdown of MIA3 ameliorates femoral artery wire injury-induced neointimal hyperplasia and increases brown-like perivascular adipocytes. Collectively, the data suggest that MIA3 deficiency prevents neointimal formation by decreasing VSMC proliferation, migration, and inflammation and maintaining BAT-like perivascular adipocytes in PVAT during injury-induced vascular remodeling, which provide a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.

scholarly journals Contribution of transcription factor EB to adipoRon-induced inhibition of arterial smooth muscle cell proliferation and migration

2019 ◽  
Vol 317 (5) ◽  
pp. C1034-C1047 ◽  
Author(s):  
Yun-Ting Wang ◽  
Jiajie Chen ◽  
Xiang Li ◽  
Michihisa Umetani ◽  
Yang Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Remodeling ◽  
Therapeutic Effects ◽  
Transcription Factor Eb ◽  
And Migration ◽  
Proliferation And Migration

Abnormal vascular smooth muscle cell (SMC) dedifferentiation with increased proliferation and migration during pathological vascular remodeling is associated with vascular disorders, such as atherosclerosis and in-stent restenosis. AdipoRon, a selective agonist of adiponectin receptor, has been shown to protect against vascular remodeling by preventing SMC dedifferentiation. However, the molecular mechanisms that mediate adipoRon-induced SMC differentiation are not well understood. The present study aimed to elucidate the role of transcription factor EB (TFEB), a master regulator of autophagy, in mediating adipoRon’s effect on SMCs. In cultured arterial SMCs, adipoRon dose-dependently increased TFEB activation, which is accompanied by upregulated transcription of genes involved in autophagy pathway and enhanced autophagic flux. In parallel, adipoRon suppressed serum-induced cell proliferation and caused cell cycle arrest. Moreover, adipoRon inhibited SMC migration as characterized by wound-healing retardation, F-actin reorganization, and matrix metalloproteinase-9 downregulation. These inhibitory effects of adipoRon on proliferation and migration were attenuated by TFEB gene silencing. Mechanistically, activation of TFEB by adipoRon is dependent on intracellular calcium, but it is not associated with changes in AMPK, ERK1/2, Akt, or molecular target of rapamycin complex 1 activation. Using ex vivo aortic explants, we demonstrated that adipoRon inhibited sprouts that had outgrown from aortic rings, whereas lentiviral TFEB shRNA transduction significantly reversed this effect of adipoRon on aortic rings. Taken together, our results indicate that adipoRon activates TFEB signaling that helps maintain the quiescent and differentiated status of arterial SMCs, preventing abnormal SMC dedifferentiation. This study provides novel mechanistic insights into understanding the therapeutic effects of adipoRon on TFEB signaling and pathological vascular remodeling.

Loss of milk fat globule-epidermal growth factor 8 (MFG-E8) in mice leads to low bone mass and accelerates ovariectomy-associated bone loss by increasing osteoclastogenesis

Bone ◽  
2015 ◽  
Vol 76 ◽  
pp. 107-114 ◽  
Author(s):  
Kathrin Sinningen ◽  
Elise Albus ◽  
Sylvia Thiele ◽  
Sylvia Grossklaus ◽  
Thomas Kurth ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Bone Loss ◽  
Bone Mass ◽  
Milk Fat ◽  
Low Bone Mass ◽  
Milk Fat Globule ◽  
Epidermal Growth ◽  
Fat Globule
Sign in / Sign up

Export Citation Format

Share Document