Consistent Biomechanical Phenotyping of Common Carotid Arteries from Seven Genetic, Pharmacological, and Surgical Mouse Models

Bersi, Matthew R.; Ferruzzi, Jacopo; Eberth, John F.; Gleason, Rudolph L.; Humphrey, Jay D.

doi:10.1007/s10439-014-0988-6

Cited by 43 publications

(40 citation statements)

References 57 publications

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“…For example, interstitial arterial cells (that is, smooth muscle cells and fibroblasts) establish a preferred matrix stiffness during development and then tend to maintain this value over a lifetime, at least in the absence of disease or injury 21 . Thus, arterial wall stiffness is similar within a single species despite many genetic variations or alterations in blood pressure 22 , and across multiple species (indeed, from lobsters to whales) despite large variations in ECM composition, blood pressure, and body size 23 . Similar observations hold for diverse connective tissues including tendons, skin, the heart, and so forth 24, 25 .…”

Section: Mechanobiological Phenomena In Tissuementioning

confidence: 99%

Mechanotransduction and extracellular matrix homeostasis

Humphrey

Dufresne

Schwartz

2014

Nat Rev Mol Cell Biol

1,651

1,407

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Preface Soft connective tissues at steady state are yet dynamic; resident cells continually read environmental cues and respond to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the matrix by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechano-regulation process that includes the deposition, rearrangement, or removal of matrix to maintain overall form and function. Progress toward understanding the molecular, cellular, and tissue scale effects that promote mechanical homeostasis has helped identify key questions for future research.

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Section: Mechanobiological Phenomena In Tissuementioning

confidence: 99%

Mechanotransduction and extracellular matrix homeostasis

Humphrey

Dufresne

Schwartz

2014

Nat Rev Mol Cell Biol

1,651

1,407

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“…Given the discovery that arterial smooth muscle cells and fibroblasts are highly mechanosensitive [7, 8], it is now clear that these cells work to establish and restore a preferred mechanical state at the tissue level that correlates well with a target stress or material stiffness under diverse circumstances [9]. Notwithstanding this dramatic capacity for adaptation in development and maturity, a fundamental and yet often ignored characteristic of arteries is their ability to maintain their composition, geometry, and function over long periods despite the continual turnover of cells and extracellular matrix.…”

Section: Introductionmentioning

confidence: 99%

Vascular homeostasis and the concept of mechanobiological stability

Cyron

Humphrey

2014

International Journal of Engineering Science

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Vascular mechanics has been studied in depth since the early 1970s mainly following classical concepts from continuum mechanics. Yet, an important distinction of blood vessels, in contrast to typical engineering materials, is the continuous degradation and deposition of material in these living tissues. In this paper we examine mechanical consequences of such mass turnover. Motivated by Lyapunov’s stability theory, we introduce the new concepts of mechanobiological equilibrium and stability and demonstrate that blood vessels can maintain their structure and function under physiological conditions only if new material is deposited at a certain prestress and the vessels are both mechanically and mechanobiologically stable. Moreover, we introduce the concept of mechanobiological adaptivity as a third corner stone to understand vascular behavior on a continuum level. We demonstrate that adaptivity represents a key difference between the stability of mechanobiological and typical human-made systems. Based on these ideas, we suggest a change of paradigm that can be illustrated by considering a common arterial pathology. We suggest that aneurysms can be interpreted as mechanobiological instabilities and that predictions of their rupture risk should not only consider the maximal diameter or wall stress, but also the mechanobiological stability. A mathematical analysis of the impact of the different model parameters on the so-called mechanobiological stability margin, a single scalar used to characterize mechanobiological stability, reveals that this stability increases with the characteristic time constant of mass turnover, material stiffness, and capacity for stress-dependent changes in mass production. As each of these parameters may be modified by appropriate drugs, the theory developed in this paper may guide both prognosis and the development of new therapies for arterial pathologies such as aneurysms.

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“…The development of systemic hypertension with the stiffening observed here suggests that, at least in this mouse model, arterial stiffening may be a factor underlying the pathogenesis of hypertension. Given the hemodynamic, mechanical, and structural changes, this mouse model may be a useful addition into a meta-analysis of other murine models to further understand the effects of genetic mutations on the hemodynamics, structure, and biomechanics of blood vessels (Bersi et al, 2014). …”

Section: Discussionmentioning

confidence: 99%

Mitochondria DNA mutations cause sex-dependent development of hypertension and alterations in cardiovascular function

Golob¹,

Tian²,

Wang³

et al. 2015

Journal of Biomechanics

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Aging is associated with conduit artery stiffening that is a risk factor for and can precede hypertension and ventricular dysfunction. Increases in mitochondria DNA (mtDNA) frequency have been correlated with aging. Mice with a mutation in the encoding domain (D257A) of a proof-reading deficient version of mtDNA polymerase-γ (POLG) have musculoskeletal features of premature aging and a shortened lifespan. However, few studies using these mice have investigated the effects of mtDNA mutations on cardiovascular function. We hypothesized that the proof-reading deficient mtDNA POLG leads to arterial stiffening, hypertension, and ventricular hypertrophy. Ten to twelve month-old D257A mice (n=13) and age- and sex-matched wild-type controls (n=13) were catheterized for hemodynamic and ventricular function measurements. Left common carotid arteries (LCCA) were harvested for mechanical tests followed by histology. Male D257A mice had pulmonary and systemic hypertension, arterial stiffening, larger LCCA diameter (701 ± 45 vs. 597 ± 60 μm), shorter LCCA axial length (8.96 ± 0.56 vs. 10.10 ± 0.80 mm), and reduced hematocrit (29.1 ± 6.1 vs. 41.3 ± 8.1; all p<0.05). Male and female D257A mice had biventricular hypertrophy (p<0.05). Female D257A mice did not have significant increases in pressure or arterial stiffening, suggesting that the mechanisms of hypertension or arterial stiffening from mtDNA mutations differ based on sex. Our results lend insight into the mechanisms of age-related cardiovascular disease and may point to novel treatment strategies to address cardiovascular mortality in the elderly.

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Consistent Biomechanical Phenotyping of Common Carotid Arteries from Seven Genetic, Pharmacological, and Surgical Mouse Models

Cited by 43 publications

References 57 publications

Mechanotransduction and extracellular matrix homeostasis

Mechanotransduction and extracellular matrix homeostasis

Vascular homeostasis and the concept of mechanobiological stability

Mitochondria DNA mutations cause sex-dependent development of hypertension and alterations in cardiovascular function

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