Expression of granulocyte colony-stimulating factor is induced in injured rat carotid arteries and mediates vascular smooth muscle cell migration

2005 ◽  
Vol 288 (1) ◽  
pp. C81-C88 ◽  
Author(s):  
Xing Chen ◽  
Sheri E. Kelemen ◽  
Michael V. Autieri
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Balloon Angioplasty ◽  
Carotid Arteries ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Important Mediator ◽  
Stimulating Factor

Granulocyte colony-stimulating factor (G-CSF) is a lineage-restricted hematopoietic growth factor that stimulates proliferation and maturation of hematopoietic progenitors and is a known powerful mobilizer of bone marrow-derived stem cells. Very little has been reported on G-CSF expression and modulation of vascular smooth muscle cell (VSMC) activation. The purpose of this study was to characterize the expression and effects of G-CSF on primary human VSMC and balloon angioplasty-injured rat carotid arteries. In cultured human VSMC, G-CSF mRNA and protein expression are induced by several cytokines, with the most potent being fetal calf serum and T-lymphocyte-conditioned media. G-CSF is not expressed in naive rat carotid arteries but is induced in neointimal SMC in carotid arteries subject to balloon angioplasty. G-CSF is chemotactic for human VSMC. There is a significant difference between unstimulated cells and those treated with G-CSF at 100 and 1,000 pg/ml ( P < 0.01 and 0.05 for 3 experiments). G-CSF also activates the GTPase Rac1, a regulator of cellular migration in VSMC. Inhibition of Rac1 inhibits G-CSF-driven VSMC migration. Important signal transduction protein kinases, including p44/42 MAPK, Akt, and S6 kinase, are also activated in response to G-CSF. This is the first report describing the expression of G-CSF in injured arteries and the multiple effects of G-CSF on VSMC activation. Together, our data suggest that G-CSF is an important mediator of inflammatory cell-VSMC communication and VSMC autocrine activation and may be an important mediator of the VSMC response to injury.

scholarly journals An essential role of PDCD4 in vascular smooth muscle cell apoptosis and proliferation: implications for vascular disease

2010 ◽  
Vol 298 (6) ◽  
pp. C1481-C1488 ◽  
Author(s):  
Xiaojun Liu ◽  
Yunhui Cheng ◽  
Jian Yang ◽  
Thomas J. Krall ◽  
Yuqing Huo ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Carotid Arteries ◽  
Vascular Diseases ◽  
Vsmc Proliferation ◽  
Vascular Walls

It is well established that vascular smooth muscle cell (VSMC) apoptosis and proliferation are critical cellular events in a variety of human vascular diseases. However, the molecular mechanisms involved in controlling VSMC apoptosis and proliferation are still unclear. In the current study, we have found that programmed cell death 4 (PDCD4) is significantly downregulated in balloon-injured rat carotid arteries in vivo and in platelet-derived growth factor-stimulated VSMCs in vitro. Overexpression of PDCD4 via adenovirus (Ad-PDCD4) increases VSMC apoptosis in an apoptotic model induced by serum deprivation. In contrast, VSMC apoptosis is significantly decreased by knockdown of PDCD4 via its small interfering RNA. In the rat carotid arteries in vivo, VSMC apoptosis is increased by Ad-PDCD4. We have further identified that activator protein 1 is a downstream signaling molecule of PDCD4 that is associated with PDCD4-mediated effects on VSMC apoptosis. In addition, VSMC proliferation was inhibited by overexpression of PDCD4. The current study has identified, for the first time, that PDCD4 is an essential regulator of VSMC apoptosis and proliferation. The downregulation of PDCD4 expression in diseased vascular walls may be responsible for the imbalance of VSMC proliferation and apoptosis. The results indicate that PDCD4 may be a new therapeutic target in proliferative vascular diseases.

scholarly journals Local M-CSF (Macrophage Colony-Stimulating Factor) Expression Regulates Macrophage Proliferation and Apoptosis in Atherosclerosis

2020 ◽  
Author(s):  
Satyesh K. Sinha ◽  
Aika Miikeda ◽  
Zachary Fouladian ◽  
Margarete Mehrabian ◽  
Chantle Edillor ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Muscle Protein ◽  
Colony Stimulating Factor ◽  
Ki 67 ◽  
Proliferation And Apoptosis ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Objective: Previous studies have shown that deficiency of M-CSF (macrophage colony-stimulating factor; or CSF1 [colony stimulating factor 1]) dramatically reduces atherosclerosis in hyperlipidemic mice. We characterize the underlying mechanism and investigate the relevant sources of CSF1 in lesions. Approach and Results: We quantitatively assessed the effects of CSF1 deficiency on macrophage proliferation and apoptosis in atherosclerotic lesions. Staining of aortic lesions with markers of proliferation, Ki-67 and bromodeoxyuridine, revealed around 40% reduction in CSF1 heterozygous (Csf1±) as compared with WT (wild type; Csf1 +/+ ) mice. Similarly, staining with a marker of apoptosis, activated caspase-3, revealed a 3-fold increase in apoptotic cells in Csf1± mice. Next, we determined the cellular sources of CSF1 contributing to lesion development. Cell-specific deletions of Csf1 in smooth muscle cells using SM22α-Cre (smooth muscle protein 22-alpha-Cre) reduced lesions by about 40%, and in endothelial cells, deletions with Cdh5-Cre (VE-cadherin-Cre) reduced lesions by about 30%. Macrophage-specific deletion with LysM-Cre (lysozyme M-Cre), on the other hand, did not significantly reduce lesions size. Transplantation of Csf1 null (Csf1 −/ − ) mice bone marrow into Csf1 +/+ mice reduced lesions by about 35%, suggesting that CSF1 from hematopoietic cells other than macrophages contributes to atherosclerosis. None of the cell-specific knockouts affected circulating CSF1 levels, and only the smooth muscle cell deletions had any effect on the percentage monocytes in the circulation. Also, Csf1± mice did not exhibit significant differences in Ly6C high /Ly6C low monocytes as compared with Csf1 +/+ . Conclusions: CSF1 contributes to both macrophage proliferation and survival in lesions. Local CSF1 production by smooth muscle cell and endothelial cell rather than circulating CSF1 is the primary driver of macrophage expansion in atherosclerosis.

Truncated YY1 interacts with BASP1 through a 339KLK341 motif in YY1 and suppresses vascular smooth muscle cell growth and intimal hyperplasia after vascular injury

2021 ◽  
Author(s):  
Fernando S Santiago ◽  
Yue Li ◽  
Ling Zhong ◽  
Mark J Raftery ◽  
Laurence Lins ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Intimal Hyperplasia ◽  
Carotid Arteries ◽  
Neointima Formation ◽  
Balloon Injury ◽  
And Migration ◽  
Proliferation And Migration

Abstract Aims In-stent restenosis and late stent thrombosis are complications associated with the use of metallic and drug-coated stents. Strategies that inhibit vascular smooth muscle cell (SMC) proliferation without affecting endothelial cell (EC) growth would be helpful in reducing complications arising from percutaneous interventions. SMC hyperplasia is also a pathologic feature of graft stenosis and fistula failure. Our group previously showed that forced expression of the injury-inducible zinc finger (ZNF) transcription factor, yin yang-1 (YY1), comprising 414 residues inhibits neointima formation in carotid arteries of rabbits and rats. YY1 inhibits SMC proliferation without affecting EC growth in vitro. Identifying a shorter version of YY1 retaining cell-selective inhibition would make it more amenable for potential use as a gene therapeutic agent. Methods and results We dissected YY1 into a range of shorter fragments (YY1A-D, YY1Δ) and found that the first two ZNFs in YY1 (construct YY1B, spanning 52 residues) repressed SMC proliferation. Receptor binding domain analysis predicts a three-residue (339KLK341) interaction domain. Mutation of 339KLK341 to 339AAA341 in YY1B (called YY1Bm) abrogated YY1B’s ability to inhibit SMC but not EC proliferation and migration. Incubation of recombinant GST-YY1B and GST-YY1Bm with SMC lysates followed by precipitation with glutathione–agarose beads and mass spectrometric analysis identified a novel interaction between YY1B and BASP1. Overexpression of BASP1, like YY1, inhibited SMC but not EC proliferation and migration. BASP1 siRNA partially rescued SMC from growth inhibition by YY1B. In the rat carotid balloon injury model, adenoviral overexpression of YY1B, like full-length YY1, reduced neointima formation, whereas YY1Bm had no such effect. CD31+ immunostaining suggested YY1B could increase re-endothelialization in a 339KLK341-dependent manner. Conclusion These studies identify a truncated form of YY1 (YY1B) that can interact with BASP1 and inhibit SMC proliferation, migration, and intimal hyperplasia after balloon injury of rat carotid arteries as effectively as full length YY1. We demonstrate the therapeutic potential of YY1B in vascular proliferative disease.

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