Reduced Biaxial Contractility in the Descending Thoracic Aorta of Fibulin-5 Deficient Mice

Murtada, Sae‐Il; Ferruzzi, Jacopo; Yanagisawa, Hiromi; Humphrey, Jay D.

doi:10.1115/1.4032938

Cited by 35 publications

(61 citation statements)

References 30 publications

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“…Phenylephrine mediates contraction through the RhoA-ROCK pathway, consistent with reports of reduced RhoA activity in HGPS mice and the hypothesis that a disrupted LINC complex correlates with weakened cellmatrix adhesion (Hale et al, 2008). Reduced central artery contractility manifests in many conditions, including Marfan syndrome (Eberth et al, 2009), fibulin-5 deficiency (Murtada et al, 2016), induced hypertension (Korneva and Humphrey, 2019), and natural aortic ageing (Wheeler et al, 2015). Yet, vascular contractility is only attenuated, not absent, in these other cases.…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, segments from each of the four regions were isolated by blunt dissection, cannulated, and placed 22 within our custom computer-controlled testing device within a Krebs-Ringer's solution at 37 o C (for active studies) or Hank's buffered solution at room temperature (for passive studies). For the active tests, vessels were set at their in vivo length and pressurized at 90 mmHg (Murtada et al, 2016). The vessels were then contracted sequentially with two vasoactive agents: 100 mM potassium chloride (KCl), which depolarizes the cell membrane and increases intracellular calcium, and 1 μM phenylephrine (PE), which is an alpha adrenergic agonist.…”

Section: Methodsmentioning

confidence: 99%

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Paradoxical Aortic Stiffening and Subsequent Cardiac Dysfunction in Hutchinson-Gilford Progeria Syndrome

Murtada

Kawamura

Caulk

et al. 2019

Preprint

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Normal ageing progressively and differentially affects the aorta along its length (Rogers et al., 2001;, thus effects of HGPS should be quantified as a function of age and aortic location. Our aim was to biomechanically phenotype the entire aorta in adult male and female Lmna G609G/G609G mice and to evaluate associated effects on the heart. We thus quantified cardiac function and central hemodynamics in vivo as well as SMC contractility and biaxial passive aortic properties ex vivo; we also used a novel computational model to associate changes in biomechanical behavior with observed microstructural features. The implications of these findings are interpreted, in part, via direct comparisons to similar data for mice that have aged normally, have germline mutations that compromise elastic fibre integrity, a feature common in central artery ageing, or have induced hypertension, which also arises in ageing. RESULTS Systolic Cardiac Function is Normal, but PWV and Diastolic Function Become Aberrant.All control (Lmna +/+ or Wt) and progeria (Lmna G609G/G609G or G609G) mice survived to the intended 140 days (d) of age, though progeria mice were significantly smaller after ~42d ( Fig. 1A): for example, body mass at 140d was 12.1±0.8 g in female and 13.8±0.9 g in male G609G mice compared with 25.0±1.1 g in female and 30.4±2.2 g in male Wt mice (p < 0.01). The heart was similarly smaller in progeria, yet myocardial microstructure appeared normal (Fig. 1B). In vivo measurements at 140d revealed that left ventricular mass and diameter, cardiac output, and stroke volume were all significantly less in progeria (Table S1), but these metrics followed allometric scaling with body mass ( , with mass and and allometric parameters), indicative of normal function for a smaller mouse (Fig. 1C-F). Though tail-cuff blood pressure was lower in progeria ( Fig. 1G), ejection fraction and fractional shortening were similar between progeria and controls ( Fig. 1H), suggesting a preserved systolic function even in the peri-morbid period (G609G mice died by ~150d). In contrast, diastolic function was compromised near the end of life. E (peak filling velocity in early diastole) and A (atrial contraction induced filling velocity in late diastole) were lower in progeria mice at 140d, with E/A higher suggestive of diastolic dysfunction (Table S1). Moreover, E' was lower but E/E' was elevated significantly (Fig. 1I), confirming late-stage diastolic dysfunction.Proximal aortic diameters were less in progeria mice, as expected of a smaller mouse, but this metric again followed allometric scaling with body mass (Fig. 1J). Aortic lengths were less in progeria (Fig. 1K,L), but the transit time for the pulse pressure wave to travel from the aortic root to the aortic bifurcation was considerably less (Fig. 1M). Consequently, PWV was dramatically higher in late-stage progeria (Fig. 1N), trending toward significance (6.16 m/s vs. 3.68 m/s; p < 0.062) and suggesting increased central artery stiffness consistent with diastolic dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Paradoxical Aortic Stiffening and Subsequent Cardiac Dysfunction in Hutchinson-Gilford Progeria Syndrome

Murtada

Kawamura

Caulk

et al. 2019

Preprint

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“…Because of circumferential-axial coupling, contraction at a fixed pressure and axial stretch just above the in vivo value typically results in positive (i.e., tensile) axial force generation in normal vessels 23 . DTAs from Tgfbr2 disrupted mice exhibited weak or negative changes in axial force, which was either prevented or reversed by rapamycin treatment.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologically Improved Contractility Protects Against Aortic Dissection in Mice With Disrupted Transforming Growth Factor-β Signaling Despite Compromised Extracellular Matrix Properties

Ferruzzi

Murtada

et al. 2016

ATVB

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Objective Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine having diverse roles in vascular morphogenesis, homeostasis, and pathogenesis. Altered activity of and signaling through TGF-β has been implicated in thoracic aortic aneurysms and dissections, conditions characterized by a reduced structural integrity of the wall that associates with altered biomechanics and mechanobiology. We quantify and contrast the passive and active biaxial biomechanical properties of the ascending and proximal descending thoracic aorta in a mouse model of altered TGF-β signaling, with and without treatment with rapamycin. Approach and Results Postnatal disruption of the gene (Tgfbr2) that codes the type II TGF-β receptor compromises vessel-level contractility and elasticity. Daily treatment with rapamycin, an mTOR inhibitor that protects against aortic dissection in these mice, largely preserves or restores the contractile function while the passive properties remain compromised. Importantly, this increased smooth muscle contractility protects an otherwise vulnerable aortic wall from pressure-induced intramural delaminations in vitro. Conclusions Notwithstanding the protection afforded by rapamycin in vivo and in vitro, the residual mechanical dysfunctionality suggests a need for caution if rapamycin is to be considered as a potential therapeutic. There is a need for in vivo evaluations in cases of increased hemodynamic loading, including hypertension or extreme exercise, which could unduly stress a structurally vulnerable aortic wall. Given these promising early results, however, such studies are clearly warranted.

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“…Several reports of the existence of active stresses in both circumferential and axial directions of arterial walls are available, indicating that smooth muscle contraction is responsible for a multiaxial response in the vascular wall. [1,6,45,55] Structural investigations performed by [27] and [6] also suggest that smooth muscle cells form two symmetric helically arranged fiber families in the arterial wall, with a orientation distribution similar to that of collagen fibers. A statistical orientation distribution of smooth muscle fibers was addressed previously by [43] but in that study FE analyses were not used to study the 3D effects of the orientation distribution.…”

Section: Discussionmentioning

confidence: 98%

Numerical analyses of the interrelation between extracellular smooth muscle orientation and intracellular filament overlap in the human abdominal aorta

et al. 2018

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K E Y W O R D Scollagen fiber orientation, filament overlap behavior, human abdominal aorta, intracellular calcium, smooth muscle contraction, smooth muscle structure This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Reduced Biaxial Contractility in the Descending Thoracic Aorta of Fibulin-5 Deficient Mice

Cited by 35 publications

References 30 publications

Paradoxical Aortic Stiffening and Subsequent Cardiac Dysfunction in Hutchinson-Gilford Progeria Syndrome

Paradoxical Aortic Stiffening and Subsequent Cardiac Dysfunction in Hutchinson-Gilford Progeria Syndrome

Pharmacologically Improved Contractility Protects Against Aortic Dissection in Mice With Disrupted Transforming Growth Factor-β Signaling Despite Compromised Extracellular Matrix Properties

Numerical analyses of the interrelation between extracellular smooth muscle orientation and intracellular filament overlap in the human abdominal aorta

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