Computationally guided in-vitro vascular growth model reveals causal link between flow oscillations and disorganized neotissue

AbstractDisturbed shear stress is thought to be the driving factor of neointimal hyperplasia in blood vessels and grafts, for example in hemodialysis conduits. Despite the common occurrence of neointimal hyperplasia, however, the mechanistic role of shear stress is unclear. This is especially problematic in the context of in situ scaffold-guided vascular regeneration, a process strongly driven by the scaffold mechanical environment. To address this issue, we herein introduce an integrated numerical-experimental approach to reconstruct the graft–host response and interrogate the mechanoregulation in dialysis grafts. Starting from patient data, we numerically analyze the biomechanics at the vein–graft anastomosis of a hemodialysis conduit. Using this biomechanical data, we show in an in vitro vascular growth model that oscillatory shear stress, in the presence of cyclic strain, favors neotissue development by reducing the secretion of remodeling markers by vascular cells and promoting the formation of a dense and disorganized collagen network. These findings identify scaffold-based shielding of cells from oscillatory shear stress as a potential handle to inhibit neointimal hyperplasia in grafts.

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Computationally guided in-vitro vascular growth model reveals causal link between flow oscillations and disorganized neotissue

10.1101/2020.08.07.241216 ◽

2020 ◽

Author(s):

E.E. Van Haaften ◽

S. Quicken ◽

W. Huberts ◽

C.V.C. Bouten ◽

N.A. Kurniawan

Keyword(s):

Shear Stress ◽

Growth Model ◽

Neointimal Hyperplasia ◽

Cyclic Strain ◽

Causal Link ◽

Oscillatory Shear ◽

Vascular Growth ◽

Vascular Regeneration ◽

Oscillatory Shear Stress

AbstractDisturbed shear stress is thought to be the driving factor of neointimal hyperplasia in blood vessels and grafts, for example in hemodialysis conduits. Despite the common occurrence of neointimal hyperplasia, however, the mechanistic role of shear stress is unclear. This is especially problematic in the context of in situ scaffold-guided vascular regeneration, a process strongly driven by the scaffold mechanical environment. To address this issue, we herein introduce an integrated numerical-experimental approach to reconstruct the graft-host response and interrogate the mechanoregulation in dialysis grafts. Starting from patient data, we numerically analyze the biomechanics at the vein-graft anastomosis of a hemodialysis conduit. Using this biomechanical data, we show in an in vitro vascular growth model that oscillatory shear stress, in the presence of cyclic strain, favors neotissue development by reducing the secretion of remodeling markers by vascular cells and promoting the formation of a dense and disorganized collagen network. These findings identify scaffold-based shielding of cells from oscillatory shear stress as a potential handle to inhibit neointimal hyperplasia in grafts.

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Abstract 561: Dysregulation of miR-155 in Acute Oscillatory Shear Stress (OSS)-mediated Oxidative Stress, Inflammation and Endothelial Dysfunction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.561 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Islam Mohamed ◽

Sheena Thomas ◽

Kimberly Rooney ◽

Roy Sutliff ◽

Nick Willett ◽

...

Keyword(s):

Oxidative Stress ◽

Shear Stress ◽

Barrier Function ◽

Oscillatory Shear ◽

Blue Dye ◽

Down Regulation ◽

Inflammatory Stress ◽

Cytoskeleton Organization ◽

Oscillatory Shear Stress

Introduction: Shear stress forces play an integral role in dictating the endothelial cell (EC) response to changes in blood flow, pro-inflammatory response and hence development of atherosclerosis. Previously, our group has identified EC microRNA-155 (miR-155) as one of the key signature dysregulated miRNAs in areas of chronic low magnitude oscillatory shear stress (OSS) in vasculature and OSS models of in-vitro. Hypothesis: we hypothesized that acute induction of OSS mediates EC oxidative stress, inflammation and dysfunction, via dysregulation of EC miR-155. Methods: 12-week old C57B/6J mice were subjected to abdominal aortic coarctation (AAC), a unique model of acute induction of OSS, for 3 days and downstream segments of acute OSS were compared to upstream unidirectional shear stress (USS) segments of the thoracic aorta. Results: Acute OSS resulted in down regulation of EC miR-155 expression and inverse upregulation of EC RhoA and Myosin light chain kinase (MYLK), known targets of miR-155-mediated EC cytoskeleton organization, in OSS segments compared with USS. This was associated with impaired EC dependent relaxation, differential contractile response to phenylephrine, and loss of EC barrier function as evaluated by extravasation of Evans-blue dye assay. In parallel, En-face immunohistochemical staining also showed increased expression of EC nitric oxide synthase (eNOS) along with increased levels of reactive oxygen species (ROS) and nitrotyrosine (NY) formation in OSS segments compared with USS. Conclusions: Together, our studies shed light on the early changes in EC response to acute induction of OSS and resulting down-regulation of EC mir-155, including; oxidative/inflammatory stress, EC dysfunction, loss of barrier function and cytoskeletal changes. Despite the early upregulation of eNOS, it could also potentially synergize with the activation of the RhoA-MYLK pathway in EC oxidative (ROS/NY)/inflammatory stress and associated EC dysfunction. Further studies are in progress to dissect the interplay between these different pathways and their causal relationships as downstream targets of EC miR-155.

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Tissue Factor Activity Is Upregulated in Human Endothelial Cells Exposed to Oscillatory Shear Stress

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613133 ◽

2002 ◽

Vol 87 (06) ◽

pp. 1062-1068 ◽

Cited By ~ 38

Author(s):

Paolo Silacci ◽

Karima Bouzourene ◽

François Daniel ◽

Hans Brunner ◽

Daniel Hayoz ◽

...

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Protein Expression ◽

Tissue Factor ◽

Critical Role ◽

Oscillatory Shear ◽

Human Endothelial Cells ◽

Static Conditions ◽

Oscillatory Shear Stress

SummaryHemodynamic forces play a critical role in the pathogenesis of atherosclerosis as evidenced by the focal nature of the disease. Oscillatory shear stress characterizes the hemodynamic environment of plaque-prone areas as opposed to unidirectional shear stress typical of plaque-free areas. These particular flow conditions modulate atherosclerosis-related genes. Tissue factor (TF) initiates blood coagulation, contributes to vascular remodeling, and is therefore a potential contributor in the development/progression of atherosclerosis. We investigated the effect of oscillatory and unidirectional flows on TF using an in vitro perfusion system. Human endothelial cells exposed for 24 h to oscillatory shear stress, significantly increased TF mRNA, and TF protein expression (1.5-and 1.75-fold, respectively, p <0.01), and surface TF activity (twofolds-increase). Expression of TF inhibitor (TFPI), mRNA and protein, remained unchanged as compared to static conditions. Conversely, cells exposed to unidirectional shear, showed a decrease in TF activity with a significant increase in TFPI mRNA and protein expression (1.5-and 1.8-fold, respectively, p <0.01). These results show for the first time that pulsatile oscillatory shear stress induces a procoagulant phenotype of endothelial cells which may favor formation/progression of atherothrombotic lesions.

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MnSOD reduction causes mtDNA damage in HAEC under Oscillatory Shear Stress

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.1134.19 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Katherine Quigley ◽

Karen Fang ◽

Nelson Jen ◽

Rongsong Li ◽

Tzung Hsiai

Keyword(s):

Shear Stress ◽

Oscillatory Shear ◽

Mtdna Damage ◽

Oscillatory Shear Stress

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Quantifying Lymphatic Endothelial Cell Morphological Changes in Response to Fluid Shear Stress, Cyclic Strain, or Combined Stress and Strain In Vitro

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.03528 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

Caleb Davis ◽

Raghuveer Lalitha Sridhar ◽

Sanjukta Chakraborty ◽

David Zawieja ◽

Michael Moreno

Keyword(s):

Shear Stress ◽

Endothelial Cell ◽

Fluid Shear Stress ◽

Morphological Changes ◽

Cyclic Strain ◽

Lymphatic Endothelial Cell ◽

Stress And Strain ◽

Combined Stress ◽

Fluid Shear

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Quantification of Oscillatory Shear Stress from Reciprocating CSF Motion on 4D Flow Imaging

American Journal of Neuroradiology ◽

10.3174/ajnr.a6941 ◽

2021 ◽

Author(s):

S. Yamada ◽

H. Ito ◽

M. Ishikawa ◽

K. Yamamoto ◽

M. Yamaguchi ◽

...

Keyword(s):

Shear Stress ◽

Oscillatory Shear ◽

Flow Imaging ◽

4D Flow ◽

Oscillatory Shear Stress ◽

4D Flow Imaging

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Abstract 363: Lim Domain Only 4 Is a Shear-Sensitive Protein, Playing a Critical Role in Endothelial Inflammation and Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a363 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Wakako Takabe ◽

Chih-Wen Ni ◽

Dong Ju Son ◽

Noah Alberts-Grill ◽

Hanjoong Jo

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Critical Role ◽

Oscillatory Shear ◽

Lim Domain ◽

Disturbed Flow ◽

Endothelial Inflammation ◽

And Migration ◽

Oscillatory Shear Stress ◽

Stable Flow

Recently, we have shown that disturbed flow, characterized by low and oscillatory shear stress, caused by a partial ligation of mouse left carotid artery (LCA) rapidly induces atherosclerosis. Using the partial ligation model and genome-wide microarray study with aortic endothelial RNAs obtained directly from the flow-disturbed carotid arteries, we previously identified mechanosensitive genes in mouse endothelial RNA including LIM domain only 4 ( lmo4 ). Here we report that LMO4 is a shear-sensitive protein that regulates endothelial inflammation. Lmo4 was up-regulated by disturbed flow in mouse LCA compared to the contralateral right CA (RCA) exposed to stable flow. At protein levels, LMO4 expression was significantly higher not only in LCA in our surgical model but also in the lesser curvature (flow-disturbed and athero-prone region of mouse aortic arch) compared to the greater curvature (stable-flow and ather-protected region). In addition, immunohistochemical staining of LMO4 in human coronary arteries revealed that its expression is detectable only in intimal endothelial cells, but not in medial cells. While LMO4 is known as a potential oncogene and associated with growth, migration and invasion of breast cancer cells, its role in cardiovascular system is not known to our knowledge. We tested a hypothesis that LMO4 is a mechanosensitive gene and plays a critical role in regulation of endothelial cell biology. LMO4 protein expression was robustly induced by oscillatory shear stress (OS) compared to laminar shear (LS) in human umbilical vein endothelial cells (HUVEC). Treatment of HUVEC with siRNA against LMO4 significantly inhibited OS-induced inflammation and migration, but not apoptosis and cell cycle progression. Further, LMO4 siRNA treatment significantly blunted expression of VCAM-1 and interleukin-8 induced by OS in endothelial cells. These results suggest that LMO4 is a shear-induced gene that plays a critical role in OS-induced endothelial inflammation and migration, and potentially in atherosclerosis.

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