Flow-dependent cellular mechanotransduction in atherosclerosis

Conway, Daniel E.; Schwartz, Martin A.

doi:10.1242/jcs.138313

Cited by 73 publications

(60 citation statements)

References 123 publications

(133 reference statements)

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“…Apoptosis of these cells in the fibrous cap of an atherosclerotic plaque is an important step toward the vulnerable phenotype. 1,46 Furthermore, atherogenic wall shear stress, also referred to as disturbed or turbulent, is known to strongly trigger (maladaptive) changes in vascular cell subtypes, 47 which in our study was attributed to loss of miR-210. Among validated miR-210 targets, APC is an important rate-limiting component in canonical Wnt signaling, making it one of the most infamous tumor suppressor genes; loss-offunction mutations are well known to cause colon cancer.…”

Section: Eken Et Al Mir-210 Enhances Atherosclerotic Plaque Stabilitymentioning

confidence: 56%

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

Eken

Jin

Chernogubova

et al. 2017

Circulation Research

108

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Stroke is the second most common cause of death 2 and major cause of disability worldwide, 2 with survivors often depending on lifelong care. Carotid stenosis is the second most common predecessor of ischemic stroke, 3 and carotid endarterectomy (CEA; and to a lesser extent carotid artery stenting) are accepted as secondary, but also primary preventive therapy. 2,4,5 With new imaging techniques, vulnerable plaques at risk of rupture can be identified with increasing accuracy, 6 but in the majority of cases, the perioperative surgical risk of ≈3% still outweighs the risk of plaque rupture in asymptomatic carotid stenosis carriers.7 As a result, CEA and carotid artery stenting are currently unfavorable for most of these individuals.8 Detection and stabilization of a vulnerable plaque by influencing the local disease process biologically would provide a sophisticated solution for asymptomatic plaque carriers at risk of stroke. Molecular Medicine© 2016 American Heart Association, Inc. Conclusions: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.

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Section: Eken Et Al Mir-210 Enhances Atherosclerotic Plaque Stabilitymentioning

confidence: 56%

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

Eken

Jin

Chernogubova

et al. 2017

Circulation Research

108

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“…The two key factors regulating endothelial FGFR1 expression, disturbed shear stress and vessel wall inflammation, are also well-known atherosclerosis risk factors (1,5). However, the link between disturbed shear stress and endothelial FGFR1 expression has not previously been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Atherosclerosis is a progressive disorder initiated by biomechanical forces in areas of the vascular tree subjected to disturbed blood flow and a number of systemic factors, including hyperlipidemia, smoking, and diabetes (1,2). Lipid uptake by the vascular wall leads over time to a gradual buildup of atherosclerotic plaques.…”

Section: Introductionmentioning

confidence: 99%

Endothelial-to-mesenchymal transition drives atherosclerosis progression

Chen

Qin

Baeyens

et al. 2015

Journal of Clinical Investigation

Self Cite

427

504

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IntroductionAtherosclerosis is a progressive disorder initiated by biomechanical forces in areas of the vascular tree subjected to disturbed blood flow and a number of systemic factors, including hyperlipidemia, smoking, and diabetes (1, 2). Lipid uptake by the vascular wall leads over time to a gradual buildup of atherosclerotic plaques. Once formed, the plaque continues to expand, leading to a gradual restriction in lumen diameter and compromise of blood flow. Under certain conditions, plaque rupture can precipitate intravascular thrombosis, resulting in complete and sudden interruption of the arterial blood supply. The buildup, growth, and rupture of the plaque have all been associated with the presence of systemic and vascular wall inflammation (3-5). Despite strong data linking vessel wall inflammation to atherosclerosis progression, the mechanism(s) of inflammation-induced atherosclerotic disease progression remains obscure (4), while efforts to halt disease progression by antiinflammatory therapies have failed in clinical trial (3).Recent studies have documented a high incidence of endothelial-to-mesenchymal transition (EndMT) in a number of pathological conditions associated with inflammation, such as myocardial infarction (6), cerebral cavernous malformations (7), portal hypertension (8), pulmonary hypertension (9), and vascular graft failure (10, 11) among others. EndMT is characterized by a change in phenotype of normal endothelial cells (ECs) that assume the shape and properties of mesenchymal cells (fibroblasts, smooth muscle cells [SMCs]), including enhanced proliferation and migration; secretion of extracellular matrix proteins, such as fibronectin and collagen; and expression of various leukocyte adhesion molecules.TGF-β has been identified as the central player in driving EndMT progression (12, 13), but the processes leading to activation of its signaling remain poorly defined. We have previously reported that a reduction in endothelial FGF-mediated signaling induced by knockout of either the key intracellular signal mediator FGF receptor substrate 2 α (FRS2α) (10) or the primary FGF receptor in the endothelium (FGF receptor 1 [FGFR1]) (14) activates TGF-β signaling, leading to EndMT.The unusual feature of FGFR1 biology is that FGFR1's expression in ECs is affected by certain inflammatory stimuli, including IFN-γ, TNF-α, and IL-1β, that induce a profound reduction in its expression (10). Since these are precisely the inflammatory mediators found in atherosclerotic plaques, we set out to investigate the occurrence and role of EndMT in atherosclerosis.Studies in cell culture and mouse models demonstrated that both oscillatory fluid shear stress and soluble inflammatory mediators reduced FGFR1 expression and signaling and promoted TGF-β signaling and EndMT. In addition, analysis of human coronary arteries demonstrated a strong correlation among endothelial FGFR1 expression, increased TGF-β signaling, and the appearance of EndMT with the severity of atherosclerosis. Together, these findings point to...

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“…Mechanotransduction in endothelial cells is certainly relevant to cardiovascular disease and has been described in an excellent recent review (Conway and Schwartz, 2013), so this aspect will not be discussed in detail. Likewise, mechanotransduction in CMs is also important to disease progression and has been the subject of another recent review (McCain and Parker, 2011).…”

Section: Introductionmentioning

confidence: 99%

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Schroer

Merryman

2015

Journal of Cell Science

117

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Fibrotic cardiac disease, a leading cause of death worldwide, manifests as substantial loss of function following maladaptive tissue remodeling. Fibrosis can affect both the heart valves and the myocardium and is characterized by the activation of fibroblasts and accumulation of extracellular matrix. Valvular interstitial cells and cardiac fibroblasts, the cell types responsible for maintenance of cardiac extracellular matrix, are sensitive to changing mechanical environments, and their ability to sense and respond to mechanical forces determines both normal development and the progression of disease. Recent studies have uncovered specific adhesion proteins and mechano-sensitive signaling pathways that contribute to the progression of fibrosis. Integrins form adhesions with the extracellular matrix, and respond to changes in substrate stiffness and extracellular matrix composition. Cadherins mechanically link neighboring cells and are likely to contribute to fibrotic disease propagation. Finally, transition to the active myofibroblast phenotype leads to maladaptive tissue remodeling and enhanced mechanotransductive signaling, forming a positive feedback loop that contributes to heart failure. This Commentary summarizes recent findings on the role of mechanotransduction through integrins and cadherins to perpetuate mechanically induced differentiation and fibrosis in the context of cardiac disease.

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Flow-dependent cellular mechanotransduction in atherosclerosis

Cited by 73 publications

References 123 publications

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

Endothelial-to-mesenchymal transition drives atherosclerosis progression

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

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