Regulation of SMC traction forces in human aortic thoracic aneurysms

AbstractSmooth muscle cells (SMCs) usually express a contractile phenotype in the healthy aorta. However, aortic SMCs have the ability to undergo profound changes in phenotype in response to changes in their extracellular environment, as occurs in ascending thoracic aortic aneurysms (ATAA). Accordingly, there is a pressing need to quantify the mechanobiological effects of these changes at single cell level. To address this need, we applied Traction Force Microscopy (TFM) on 759 cells coming from three primary healthy (AoPrim) human SMC lineages and three primary aneurysmal (AnevPrim) human SMC lineages, from age and gender matched donors. We measured the basal traction forces applied by each of these cells onto compliant hydrogels of different stiffness (4, 8, 12, 25 kPa). Although the range of force generation by SMCs suggested some heterogeneity, we observed that: 1. the traction forces were significantly larger on substrates of larger stiffness; 2. traction forces in AnevPrim were significantly higher than in AoPrim cells. We modelled computationally the dynamic force generation process in SMCs using the motor-clutch model and found that it accounts well for the stiffness-dependent traction forces. The existence of larger traction forces in the AnevPrim SMCs were related to the larger size of cells in these lineages. We conclude that phenotype changes occurring in ATAA, which were previously known to reduce the expression of elongated and contractile SMCs (rendering SMCs less responsive to vasoactive agents), tend also to induce stronger SMCs. Future work aims at understanding the causes of this alteration process in aortic aneurysms.

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Sex and Gender in Thoracic Aortic Aneurysms and Dissection

Seminars in Thoracic and Cardiovascular Surgery ◽

10.1053/j.semtcvs.2011.08.009 ◽

2011 ◽

Vol 23 (2) ◽

pp. 124-125 ◽

Cited By ~ 13

Author(s):

Kendra J. Grubb ◽

Irving L. Kron

Keyword(s):

Aortic Aneurysms ◽

Sex And Gender ◽

Thoracic Aortic Aneurysms ◽

And Gender

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Vinculin-dependent actin bundling regulates cell migration and traction forces

Biochemical Journal ◽

10.1042/bj20140872 ◽

2015 ◽

Vol 465 (3) ◽

pp. 383-393 ◽

Cited By ~ 26

Author(s):

Karry M. Jannie ◽

Shawn M. Ellerbroek ◽

Dennis W. Zhou ◽

Sophia Chen ◽

David J. Crompton ◽

...

Keyword(s):

Cell Migration ◽

Traction Force ◽

Force Generation ◽

Actin Binding ◽

Traction Forces ◽

Cell Matrix ◽

Cell Cell

Vinculin transduces force and orchestrates mechanical signalling at cell–cell and cell–matrix adhesions. Cells expressing a mutant vinculin deficient in actin binding and bundling display migration and traction force defects. Vinculin binding to actin is critical for cell migration and force generation.

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Abstract 4275: TGFBR2 Mutations Reduce Expression of Contractile Proteins in Aortic Smooth Muscle Cells and Predispose Individuals to Thoracic Aortic Aneurysms and Dissections

Circulation ◽

10.1161/circ.118.suppl_18.s_856-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Sakiko Inamoto ◽

Callie Kwartler ◽

Andrea Lafont ◽

Yao Yun Liang ◽

Van Tran Fadulu ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Matched Control ◽

Muscle Cells ◽

Contractile Proteins ◽

Aortic Aneurysms ◽

Gain Of Function ◽

Age And Gender ◽

Thoracic Aortic Aneurysms ◽

And Gender

Mutations in the TGF-β receptor type II gene ( TGFBR2 ) cause thoracic aortic aneurysms and dissections (TAAD). Studies have suggested a gain of function effect for these mutations, leading to increased TGF-β signaling in the aortic media and resulting in vascular disease. We sought to characterize the phenotype of smooth muscle cells (SMCs) harboring heterozygous missense TGFBR2 mutations and our data suggest that instead of a gain of function, TGFBR2 mutations cause TAAD as a result of a loss of function resulting in defective SMC differentiation. Using primary aortic SMCs from patients harboring TGFBR2 mutations (n=4), we show a global decrease in expression of SMC contractile proteins ( ACTA2 , MYH11 , CNN1 , SMTN , TPM1 , TPM2 , p <0.001) by quantitative PCR analysis when these cells are compared with age and gender matched control SMCs (n=4), along with no change in the expression of cytoskeletal proteins. Consistent with the decreased expression of contractile proteins in the mutant cells, there was increased expression of S100A4, a marker of de-differentiated SMCs (p<0.001). Analysis of fixed and frozen aortas from patients with TGFBR2 mutations (n=3) confirmed decreased in vivo expression of SMC contractile proteins when compared to control aortas (n=3). In control SMCs, addition of TGF- β significantly increased the expression of the SMC contractile proteins but the TGFBR2 SMCs showed no significant increase in expression of these proteins with TGF-β stimulation. We found that fibroblasts explanted from patients with TGFBR2 mutations (n=8) consistently fail to transform into myofibroblasts as assessed by expression of SMC contractile proteins after TGF-β stimulation, when compared with age and gender matched control fibroblasts (n=8). Finally, introduction of TGFBR2 missense mutations into a mouse mesenchymal embryonic cell line that is used as a model of SMC differentiation (10T1/2 cells) disrupts the expression of contractile proteins in these cells when assessed post-differentiation. These data suggest that TGFBR2 mutations disrupt differentiation of SMCs and myofibroblasts. This is the first genetic defect identified to lead to defective SMC differentiation.

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Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.116.303229 ◽

2017 ◽

Vol 37 (1) ◽

pp. 26-34 ◽

Cited By ~ 74

Author(s):

Dianna M. Milewicz ◽

Kathleen M. Trybus ◽

Dong-chuan Guo ◽

H. Lee Sweeney ◽

Ellen Regalado ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Aortic Aneurysms ◽

Force Generation ◽

Thoracic Aortic Aneurysms ◽

Cell Force

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The genetics and biomechanics of thoracic aortic diseases

Vascular Biology ◽

10.1530/vb-19-0027 ◽

2019 ◽

Vol 1 (1) ◽

pp. R13-R25

Author(s):

Amer Harky ◽

Ka Siu Fan ◽

Ka Hay Fan

Keyword(s):

Structural Instability ◽

Aortic Aneurysms ◽

Telomere Dysfunction ◽

Aortic Diseases ◽

Thoracic Aortic Aneurysms ◽

Treatment And Prevention ◽

Inflammatory State ◽

Biomechanical Changes ◽

Thoracic Aneurysms ◽

Aortic Dissections

Thoracic aortic aneurysms and aortic dissections (TAAD) are highly fatal emergencies within cardiothoracic surgery. With increasing age, thoracic aneurysms become more prevalent and pose an even greater threat when they develop into aortic dissections. Both diseases are multifactorial and are influenced by a multitude of physiological and biomechanical processes. Structural stability of aorta can be disrupted by genes, such as those for extracellular matrix and contractile protein, as well as telomere dysfunction, which leads to senescence of smooth muscle and endothelial cells. Biomechanical changes such as increased luminal pressure imposed by hypertension are also very prevalent and lead to structural instability. Furthermore, ageing is associated with a pro-inflammatory state that exacerbates degeneration of vessel wall, facilitating the development of both aortic aneurysms and aortic dissection. This literature review provides an overview of the aetiology and pathophysiology of both thoracic aneurysms and aortic dissections. With an improved understanding, new therapeutic targets may eventually be identified to facilitate treatment and prevention of these diseases.

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Dynamics of force generation by spreading platelets

Soft Matter ◽

10.1039/c8sm00895g ◽

2018 ◽

Vol 14 (31) ◽

pp. 6571-6581 ◽

Cited By ~ 10

Author(s):

Jana Hanke ◽

Dimitri Probst ◽

Assaf Zemel ◽

Ulrich S. Schwarz ◽

Sarah Köster

Keyword(s):

Internal Stress ◽

Traction Force ◽

Variable Stiffness ◽

Human Platelets ◽

Force Generation ◽

Dynamic Force ◽

Time Resolved ◽

Force Microscopy ◽

Elastic Substrates ◽

High Level

Using time-resolved traction force microscopy on soft elastic substrates of variable stiffness, here we show that human platelets generate highly dynamic force patterns and an exceptionally high level of internal stress.

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Glutathione system participation in thoracic aneurysms from patients with Marfan syndrome

VASA ◽

10.1024/0301-1526/a000609 ◽

2017 ◽

Vol 46 (3) ◽

pp. 177-186 ◽

Cited By ~ 8

Author(s):

Alejandra María Zúñiga-Muñoz ◽

Israel Pérez-Torres ◽

Verónica Guarner-Lans ◽

Elías Núñez-Garrido ◽

Rodrigo Velázquez Espejel ◽

...

Keyword(s):

Aortic Aneurysm ◽

Marfan Syndrome ◽

Aortic Aneurysms ◽

Aortic Dilatation ◽

Glutathione S Transferase ◽

Reduced And Oxidized Glutathione ◽

Total Antioxidant ◽

Elevated Activity ◽

Acute Dissection ◽

Thoracic Aneurysms

Abstract. Background: Aortic dilatation in Marfan syndrome (MFS) is progressive. It is associated with oxidative stress and endothelial dysfunction that contribute to the early acute dissection of the vessel and can result in rupture of the aorta and sudden death. We evaluated the participation of the glutathione (GSH) system, which could be involved in the mechanisms that promote the formation and progression of the aortic aneurysms in MFS patients. Patients and methods: Aortic aneurysm tissue was obtained during chest surgery from eight control subjects and 14 MFS patients. Spectrophotometrical determination of activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR), lipid peroxidation (LPO) index, carbonylation, total antioxidant capacity (TAC), and concentration of reduced and oxidized glutathione (GSH and GSSG respectively), was performed in the homogenate from aortic aneurysm tissue. Results: LPO index, carbonylation, TGF-β1, and GR activity were increased in MFS patients (p < 0.04), while TAC, GSH/GSSG ratio, GPx, and GST activity were significantly decreased (p < 0.04). Conclusions: The depletion of GSH, in spite of the elevated activity of GR, not only diminished the activity of GSH-depend GST and GPx, but increased LPO, carbonylation and decreased TAC. These changes could promote the structural and functional alterations in the thoracic aorta of MFS patients.

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