Smooth muscle cells in porcine vein graft intimal hyperplasia are derived from the local vessel wall

The vessel wall is a dynamic tissue that undergoes positive remodelling in response to altered mechanical stress. A typical example is vein graft remodelling, because veins do not develop arteriosclerosis until a vein segment is grafted on to arteries. In this process, it was observed that vascular endothelial and smooth muscle cells of vein grafts die due to suddenly elevated blood pressure. This cell death is followed by endothelial regeneration. Central to this theme is the essential role played by EPCs (endothelial progenitor cells) in regenerating the lost endothelium. The mechanisms by which EPCs attach to the vessel wall and differentiate into mature endothelial cells involve increased chemokine production and laminar shear flow stimulation on the vessel wall. It seems that neo-endothelial cells derived from EPCs lack mature cell functions and express high levels of adhesion molecules resulting in LDL (low-density lipoprotein) penetration and mononuclear cell infiltration into the sub-endothelial space. Among infiltrated mononuclear cells, there are smooth muscle progenitors that proliferate and differentiate into smooth muscle cells. Meanwhile, stem cells present in the media and adventitia may also migrate into arteriosclerotic lesions via the vasa vasorum that are abundant in the diseased vessels. However, the molecular events leading to the homing, differentiation and maturation of stem/progenitor cells still needs elucidation. The present review attempts to update the progress in stem cell research related to the pathogenesis of vein graft arteriosclerosis or remodelling, focusing on the mechanisms by which stem/progenitor cells participate in the development of lesions, and to discuss the controversial issues and the future perspectives surrounding this research area.

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Thrombin Inhibition and Thrombin Generation by Cultured Aortic Endothelial and Smooth Muscle Cells from Minipig

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657227 ◽

1982 ◽

Vol 48 (01) ◽

pp. 101-103 ◽

Cited By ~ 1

Author(s):

B Kirchhof ◽

J Grünwald

Keyword(s):

Endothelial Cells ◽

Smooth Muscle ◽

Smooth Muscle Cells ◽

Vessel Wall ◽

Thrombin Generation ◽

Muscle Cells ◽

Thrombin Inhibition ◽

Generating Capacity ◽

Wall Interaction ◽

Cells Cultured

SummaryEndothelial and smooth muscle cells cultured from minipig aorta were examined for their inhibitory activity on thrombin and for their thrombin generating capacity.Endothelial cells showed both a thrombin inhibition and an activation of prothrombin in the presence of Ca++, which was enhanced in the presence of phospholipids. Smooth muscle cells showed an activation of prothrombin but at a lower rate. Both coagulation and amidolytic micro-assays were suitable for studying the thrombin-vessel wall interaction.

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Abstract 169: Smad3 Drives Cross-Talk Between TGFß and Wnt/ß-Catenin Signaling Pathways in Smooth Muscle Cells

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.169 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Daniel M DiRenzo ◽

Xu Dong Shi ◽

Lian-Wang Guo ◽

K Craig Kent

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Wnt Signaling ◽

Vascular Injury ◽

Cross Talk ◽

Intimal Hyperplasia ◽

Muscle Cells ◽

Arterial Injury ◽

Protein Levels ◽

Qrt Pcr

Restenosis (neo-intimal hyperplasia) occurs in approximately 25-50% of patients undergoing arterial interventions, primarily due to the proliferation and migration of arterial smooth muscle cells (SMCs) into the peri-luminal area. Recently, Wnt/β-catenin signaling has been shown to promote SMC proliferation and enhance neo-intimal hyperplasia but its mechanism of activation is unclear. Interestingly, Wnt/β-catenin has been shown to be activated by TGFβ in mesenchymal stem cells and fibroblasts. We have shown that TGFβ and its downstream signaling protein, Smad3, are upregulated following vascular injury and that Smad3 overexpressing SMCs display enhanced proliferation, migration, and neo-intimal hyperplasia. These results led us to hypothesize that TGFβ, through Smad3, activates Wnt/β-catenin to regulate SMC behavior following arterial injury . In primary rat SMCs, TGFβ (5ng/mL) led to β-catenin activation and relocalization from the plasma membrane to the cytoplasm / nucleus within 24 hours. Furthermore, qRT-PCR results demonstrated that expression of Wnt11 (22 fold) and Wnt9a (3.9 fold) were significantly upregulated after 24 hours of TGFβ stimulation (p<0.05, n=3). In addition, 24 hours of TGFβ stimulation in SMCs overexpressing Smad3 (TGFβ/Smad3) further enhanced the gene expression of Wnt11 (>300 fold) and Wnt9a (14 fold) and also stimulated significant increases in Wnt2b (41 fold), Wnt5a (2.9 fold), and Wnt4 (3.2 fold) (p<0.05, n=3) as measured by qRT-PCR. Western blot results demonstrated that the combined TGFβ/Smad3 stimulation increased β-catenin protein levels, suggesting that TGFβ activates canonical Wnt signaling leading to stabilization of β-catenin protein. In normal rat carotid arteries, β-catenin protein was undetectable via immunohistochemistry but could be seen in SMCs of the vessel media at 3 days post-balloon angioplasty and in neo-intimal cells at 7 and 14 days. Smad3 was also expressed in neo-intimal cells at 7 and 14 days post-angioplasty suggesting that TGFβ, through Smad3, is responsible for Wnt/β-Catenin activation during vascular injury. In conclusion, this work describes a novel cross-talk in SMCs between TGFβ and Wnt signaling which may provide a viable target for future anti-restenotic treatments.

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Matrix Gla Protein Synthesis and Gamma-carboxylation in the Aortic Vessel Wall and Proliferating Vascular Smooth Muscle Cells

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614911 ◽

1999 ◽

Vol 82 (12) ◽

pp. 1764-1767 ◽

Cited By ~ 50

Author(s):

Dean Cain ◽

David Sane ◽

Reidar Wallin

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Vitamin K ◽

Vessel Wall ◽

Arterial Wall ◽

Muscle Cells ◽

Matrix Gla Protein ◽

Dt Diaphorase

SummaryMatrix GLA protein (MGP) is an inhibitor of calcification in the arterial wall and its activity is dependent upon vitamin K-dependent γ-carboxylation. This modification is carried out by a warfarin sensitive enzyme system that converts specific Glu residues to γ-carboxyglutamic acid (GLA) residues. Recent studies have demonstrated that the γ-carboxylation system in the arterial wall, in contrast to that in the liver, is unable to use vitamin K as an antidote to warfarin.By use of immunohistochemistry we demonstrate that MGP is expressed in the arterial wall and immunocytochemistry localized the MGP precursors to the endoplasmic reticulum in vascular smooth muscle cells. Resting smooth vascular muscle cells in the aortic wall and proliferating cells from explants of the aorta have all the enzymes needed for γ-carboxylation of MGP. However, when compared to the liver system, expression of the enzymes of the γ-carboxylation system in vascular smooth muscle cells is different. Of particular interest is the finding that the specific activity of the warfarin sensitive enzyme vitamin K epoxide reductase is 3-fold higher in vascular smooth muscle cells than in liver. DT-diaphorase, which catalyses the antidotal pathway for vitamin K reduction in liver, is 100-fold less active in resting vascular smooth muscle cells than in liver. Data obtained from an in vitro γ-carboxylation system suggest that the antidotal pathway catalyzed by DT-diaphorase in the vessel wall is unable to provide the carboxylase with enough reduced vitamin K to trigger γ-carboxylation of MGP. This finding provides an explanation to the inability of vitamin K to work as an antidote to warfarin intoxication of the arterial wall. Therefore the vitamin K dependent γ-carboxylation system in the arterial wall share a common feature with the system in bone cells by being unable to utilize vitamin K as an antidote.

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Smooth Muscle Cells in Atherosclerosis Originate From the Local Vessel Wall and Not Circulating Progenitor Cells in ApoE Knockout Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/01.atv.0000247243.48542.9d ◽

2006 ◽

Vol 26 (12) ◽

pp. 2696-2702 ◽

Cited By ~ 164

Author(s):

Jacob F. Bentzon ◽

Charlotte Weile ◽

Claus S. Sondergaard ◽

Johnny Hindkjaer ◽

Moustapha Kassem ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Progenitor Cells ◽

Knockout Mice ◽

Vessel Wall ◽

Muscle Cells ◽

Apoe Knockout Mice

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Peri-Adventitial Delivery of Smooth Muscle Cells in Porous Collagen Scaffolds for Treatment of Experimental Abdominal Aortic Aneurysm

Biomaterials Science ◽

10.1039/d1bm00685a ◽

2021 ◽

Author(s):

Joscha Mulorz ◽

Mahdis Shayan ◽

Caroline Hu ◽

Cynthia Alcazar ◽

Alex H.P Chan ◽

...

Keyword(s):

Smooth Muscle ◽

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Vessel Wall ◽

Muscle Cells ◽

Collagen Scaffolds ◽

Abdominal Aortic ◽

Direct Delivery

Abdominal aortic aneurysm (AAA) is associated with the loss of vascular smooth muscle cells (SMCs) within the vessel wall. Direct delivery of therapeutic cells is challenging due to impaired mechanical...

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Kv1.3 blockade inhibits proliferation of vascular smooth muscle cells in vitro and intimal hyperplasia in vivo

Translational Research ◽

10.1016/j.trsl.2020.06.002 ◽

2020 ◽

Vol 224 ◽

pp. 40-54 ◽

Cited By ~ 1

Author(s):

Joaquim Bobi ◽

Manel Garabito ◽

NÚria Solanes ◽

Pilar Cidad ◽

Víctor Ramos-Pérez ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Intimal Hyperplasia ◽

Muscle Cells

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Function and role of voltage-gated sodium channel NaV1.7 expressed in aortic smooth muscle cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00960.2008 ◽

2009 ◽

Vol 296 (1) ◽

pp. H211-H219 ◽

Cited By ~ 22

Author(s):

Kentaro Meguro ◽

Haruko Iida ◽

Haruhito Takano ◽

Toshihiro Morita ◽

Masataka Sata ◽

...

Keyword(s):

Smooth Muscle ◽

Cell Migration ◽

Smooth Muscle Cells ◽

Intimal Hyperplasia ◽

Muscle Cells ◽

Rt Pcr ◽

Balloon Injury ◽

Aortic Smooth Muscle Cells ◽

Aortic Smooth Muscle ◽

Voltage Gated

Voltage-gated Na+ channel currents ( INa) are expressed in several types of smooth muscle cells. The purpose of this study was to evaluate the expression of INa, its functional role, pathophysiology in cultured human (hASMCs) and rabbit aortic smooth muscle cells (rASMCs), and its association with vascular intimal hyperplasia. In whole cell voltage clamp, INa was observed at potential positive to −40 mV, was blocked by tetrodotoxin (TTX), and replacing extracellular Na+ with N-methyl-d-glucamine in cultured hASMCs. In contrast to native aorta, cultured hASMCs strongly expressed SCN9A encoding NaV1.7, as determined by quantitative RT-PCR. INa was abolished by the treatment with SCN9A small-interfering (si)RNA ( P < 0.01). TTX and SCN9A siRNA significantly inhibited cell migration ( P < 0.01, respectively) and horseradish peroxidase uptake ( P < 0.01, respectively). TTX also significantly reduced the secretion of matrix metalloproteinase-2 6 and 12 h after the treatment ( P < 0.01 and P < 0.05, respectively). However, neither TTX nor siRNA had any effect on cell proliferation. L-type Ca2+ channel current was recorded, and INa was not observed in freshly isolated rASMCs, whereas TTX-sensitive INa was recorded in cultured rASMCs. Quantitative RT-PCR and immunostaining for NaV1.7 revealed the prominent expression of SCN9A in cultured rASMCs and aorta 48 h after balloon injury but not in native aorta. In conclusion, these studies show that INa is expressed in cultured and diseased conditions but not in normal aorta. The NaV1.7 plays an important role in cell migration, endocytosis, and secretion. NaV1.7 is also expressed in aorta after balloon injury, suggesting a potential role for NaV1.7 in the progression of intimal hyperplasia.

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Defective autophagy in vascular smooth muscle cells increases passive stiffness of the mouse aortic vessel wall

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s00424-020-02408-y ◽

2020 ◽

Vol 472 (8) ◽

pp. 1031-1040 ◽

Cited By ~ 1

Author(s):

Dorien G. De Munck ◽

Arthur J.A. Leloup ◽

Guido R. Y. De Meyer ◽

Wim Martinet ◽

Paul Fransen

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Vessel Wall ◽

Muscle Cells ◽

Passive Stiffness

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Platelet And Smooth Muscle Cell Responses After Endothelial Desquamation

10.1055/s-0038-1652729 ◽

1981 ◽

Author(s):

M B Stemerman

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Abdominal Aorta ◽

Vessel Wall ◽

Balloon Catheter ◽

Muscle Cells ◽

Mechanical Removal ◽

Cell Counts ◽

Old Rats

Although compromise of endothelial integrity occurs through many mechanisms, mechanical removal by balloon catheter is an excellent experimental method to study vascular responsiveness after injury. The interaction of platelets with the vessel wall, as well as proliferation of vascular smooth muscle cells can be assessed in this model. Following platelet attachment to the subendothelium, platelets release materials from their alpha granules. Using an antibody raised against platelet factor 4, a protein stored in alpha granules, we have demonstrated that material released from platelets do enter the vessel wall. A large amount of PF 4 antigen enters the wall shortly after endothelial removal, permeating the wall completely by 30 minutes, but little trace of the antigen can be found four hours after injury. Using infusions of PGI2 to a level of 850 ng/kg/min in rabbits, in vivo platelet adhesion to the exposed subendothelium can be greatly reduced and release of PF4 antigen into the vessel wall markedly diminished. Growth of smooth muscle cells (SMC) after endothelial removal has also been measured by 3H-Thymidine labeling of SMC DNA. As measured by this method as well as direct cell counts, SMC proliferation in the abdominal aorta is significantly greater than the thoracic. Reinjury of only the abdominal aorta by balloon catheter 4 days after the initial total aortic injury causes a proliferative spurt in the thoracic aortic SMC, thus demonstrating that a humoral signal can initiate SMC proliferation. In addition, the response of SMC from 21 month old rats when compared with 3 month old rats is much greater. These studies demonstrate in vivo methods for examining the response of platelets and SMC following endothelial injury. Further, these studies indicate that the response to injury hypothesis of atherosclerosis progression should now be broadened to the concept of a response to signal view of atherogenesis.

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