Biomechanical roles of medial pooling of glycosaminoglycans in thoracic aortic dissection

Roccabianca, Sara; Ateshian, Gerard A.; Humphrey, Jay D.

doi:10.1007/s10237-013-0482-3

Cited by 102 publications

(101 citation statements)

References 71 publications

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“…[18]). Hence, phenomenological continuum models can serve as useful tools for studying parametrically the consequences of changes in Donnan swelling pressures, that is, imposed local changes in volume (detF = 1).…”

Section: Continuum Modelmentioning

confidence: 99%

“…Pathological accumulations of these GAG/PG aggregates could overload these connections, however, thus resulting in compromised or lost mechanosensing. Indeed, in the extreme cases of localized pooling of these aggregates, a complete loss of fibre -cell connections may result in smooth muscle anoikis [17] or cause high-stress concentrations that could adversely affect the structural integrity of the wall and lead to delaminations [18].…”

Section: Introductionmentioning

confidence: 99%

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Computational modelling suggests good, bad and ugly roles of glycosaminoglycans in arterial wall mechanics and mechanobiology

Roccabianca

Bellini

Humphrey

2014

J. R. Soc. Interface.

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The medial layer of large arteries contains aggregates of the glycosaminoglycan hyaluronan and the proteoglycan versican. It is increasingly thought that these aggregates play important mechanical and mechanobiological roles despite constituting only a small fraction of the normal arterial wall. In this paper, we offer a new hypothesis that normal aggregates of hyaluronan and versican pressurize the intralamellar spaces, and thereby put into tension the radial elastic fibres that connect the smooth muscle cells to the elastic laminae, which would facilitate mechanosensing. This hypothesis is supported by novel computational simulations using two complementary models, a mechanistically based finite-element mixture model and a phenomenologically motivated continuum hyperelastic model. That is, the simulations suggest that normal aggregates of glycosaminoglycans/proteoglycans within the arterial media may play equally important roles in supporting (i.e. a structural role) and sensing (i.e. an instructional role) mechanical loads. Additional simulations suggest further, however, that abnormal increases in these aggregates, either distributed or localized, may over-pressurize the intralamellar units. We submit that these situations could lead to compromised mechanosensing, anoikis and/or reduced structural integrity, each of which represent fundamental aspects of arterial pathologies seen, for example, in hypertension, ageing and thoracic aortic aneurysms and dissections.

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Section: Continuum Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Computational modelling suggests good, bad and ugly roles of glycosaminoglycans in arterial wall mechanics and mechanobiology

Roccabianca

Bellini

Humphrey

2014

J. R. Soc. Interface.

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“…[6], Yang and colleagues showed that an upregulation of TGF-b (transforming growth factor beta) leads to increased lipid-binding proteoglycans, which in turn can accelerate atherosclerosis in diabetic patients. Previous theoretical studies suggested further that increased GAGs can affect the aortic wall in ways ranging from altering residual stresses to increasing the propensity for dissection [7][8][9]. There is, therefore, a pressing need to investigate further the potential consequences of GAGs on arterial behavior.…”

Section: Introductionmentioning

confidence: 99%

Local Versus Global Mechanical Effects of Intramural Swelling in Carotid Arteries

Sorrentino

Fourman

Ferruzzi

et al. 2015

Journal of Biomechanical Engineering

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Glycosaminoglycans (GAGs) are increasingly thought to play important roles in arterial mechanics and mechanobiology. We recently suggested that these highly negatively charged molecules, well known for their important contributions to cartilage mechanics, can pressurize intralamellar units in elastic arteries via a localized swelling process and thereby impact both smooth muscle mechanosensing and structural integrity. In this paper, we report osmotic loading experiments on murine common carotid arteries that revealed different degrees and extents of transmural swelling. Overall geometry changed significantly with exposure to hypo-osmotic solutions, as expected, yet mean pressure-outer diameter behaviors remained largely the same. Histological analyses revealed further that the swelling was not always distributed uniformly despite being confined primarily to the media. This unexpected finding guided a theoretical study of effects of different distributions of swelling on the wall stress. Results suggested that intramural swelling can introduce highly localized changes in the wall mechanics that could induce differential mechanobiological responses across the wall. There is, therefore, a need to focus on local, not global, mechanics when examining issues such as swelling-induced mechanosensing.

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“…34 The model also provides an intriguing explanation for the detection of foci of GAGs in the outer media of diseased aortas, which are considered to induce significant stress concentrations and intralamellar Donnan swelling pressures. 35,36 The mechanism behind increased detection of GAGs is unknown, but the current paradigm refers to increased GAG production. 37,38 The model presented here suggests an additional or alternative mechanism whereby access of fluid to the interstitial space (secondary to alteration of microvascular tone and Pif) will inevitably induce swelling of the osmotically active and underhydrated GAGs, leading to expansion of the vessel area occupied by GAGs.…”

Section: Pathophysiological Predictions Of the Modelmentioning

confidence: 99%

“…35,36 The mechanism behind increased detection of GAGs is unknown, but the current paradigm refers to increased GAG production.…”

mentioning

confidence: 99%

Role of Microvascular Tone and Extracellular Matrix Contraction in the Regulation of Interstitial Fluid

Mallat

Tedgui

Henrion

2016

ATVB

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G enetic mutations that predispose to thoracic aortic aneurysms and aortic dissections (TAADs) affect structural components of the extracellular matrix (ECM), transmembrane structures involved in mechanical integrity, mechanosensing, and signal transduction, or intracellular components of the cell contractile apparatus. [1][2][3] Concepts and studies are being developed to explain how such alterations may impact the response of the aorta to hemodynamic stress and drive abnormal aortic remodeling. 4 Here, we propose a focus shift toward the small vessels (arterioles and vasa vasorum) to explain, based on current knowledge about the (patho)physiology of blood flow regulation and fluid dynamics, how alterations in ECM and the cell contractile apparatus may instigate the frightening process of aortic dissection. Microcirculatory Vascular Tone and the Autoregulation of Blood Flow: The Example of Myogenic ToneMicrocirculatory vascular tone is the main determinant of vascular resistance and ensures tissue perfusion in response to changing metabolic demands. An increase in pressure induces a rapid and reversible vasoconstriction of small resistance vessels, an intrinsic property because of their ability to develop myogenic tone (MT). 5 Besides protecting downstream capillaries from abrupt increases in blood pressure occurring in larger vessels, MT has a key role in the inward eutrophic vascular remodeling in response to a chronic rise in pressure.Pressure induces deformation of cell membrane proteins such as stretch-activated ion channels; conformational changes in matrix and cytoskeletal proteins; activation of ECM and integrins; and activation of various cellular junctions (Figure 1). Vascular smooth muscle cell (SMC) depolarization and calcium entry are necessary for the development of pressure-induced contraction and myogenic tone. Although the nature of the channel(s) involved in MT development remains debated, canonical transient receptor potential (TRP) channels are strong candidates. Interactions of TRP polycystin 1 and 2 (TRPP1 and TRPP2) with filamin A, an actin crosslinking protein, are critical for stretch-activated ion channel regulation and MT development.6 Indirect evidence for a role of chloride © 2016 American Heart Association, Inc. Abstract-The pathophysiology of aortic dissection is poorly understood, and its risk is resistant to medical treatment. Most studies have focused on a proposed pathogenic role of transforming growth factor-β in Marfan disease and related thoracic aortic aneurysms and aortic dissections. However, clinical testing of this concept using angiotensin II type 1 receptor antagonists to block transforming growth factor-β signaling fell short of promise. Genetic mutations that predispose to thoracic aortic aneurysms and aortic dissections affect components of the extracellular matrix and proteins involved in cellular force generation. Thus, a role for dysfunctional mechanosensing in abnormal aortic wall remodeling is emerging. However, how abnormal mechanosensing leads to aortic dis...

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Biomechanical roles of medial pooling of glycosaminoglycans in thoracic aortic dissection

Cited by 102 publications

References 71 publications

Computational modelling suggests good, bad and ugly roles of glycosaminoglycans in arterial wall mechanics and mechanobiology

Computational modelling suggests good, bad and ugly roles of glycosaminoglycans in arterial wall mechanics and mechanobiology

Local Versus Global Mechanical Effects of Intramural Swelling in Carotid Arteries

Role of Microvascular Tone and Extracellular Matrix Contraction in the Regulation of Interstitial Fluid

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