Effect of an acute mechanical stimulus on aortic structure in the transverse aortic constriction mouse model

Chen, Jing; Wu, Jian; Li, Lei; Zou, Yunzeng; Zhu, Dongsheng; Gao, Pingjin

doi:10.1111/j.1440-1681.2011.05544.x

Cited by 21 publications

(19 citation statements)

References 31 publications

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“…In keeping with this, in mice subjected to transverse aortic constriction, adventitial collagen deposition is observed proximal to the constriction, where pressures are elevated, but not distal to the constriction where pressures are normal. 49 Likewise, a recent finding suggest that mild hypertension in children predisposes to increasesd pulse wave velocity in adulthood. 50 No matter the cause, stiffening of the proximal aorta leads to the loss of Windkessel effect, further elevating systolic blood pressure.…”

Section: Discussionmentioning

confidence: 98%

Inflammation and Mechanical Stretch Promote Aortic Stiffening in Hypertension Through Activation of p38 Mitogen-Activated Protein Kinase

Thabet

Kirabo

et al. 2014

Circulation Research

214

187

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Rationale Aortic stiffening commonly occurs in hypertension and further elevates systolic pressure. Hypertension is also associated with vascular inflammation and increased mechanical stretch. The interplay between inflammation, mechanical stretch and aortic stiffening in hypertension remains undefined. Objective To determine the role of inflammation and mechanical stretch in aortic stiffening. Methods and Results Chronic angiotensin II infusion caused marked aortic adventitial collagen deposition, as quantified by Masson’s Trichrome Blue staining and biochemically by hydroxyproline content, in wild-type (WT) but not in Recombination Activation Gene-1 deficient (RAG-1−/−) mice. Aortic compliance, defined by ex-vivo measurements of stress-strain curves, was reduced by chronic angiotensin II infusion in WT mice (p<0.01) but not in RAG-1−/− mice (p<0.05). Adoptive transfer of T cells to RAG-1−/− mice restored aortic collagen deposition and stiffness to values observed in WT mice. Mice lacking the T cell derived cytokine IL-17a were also protected against aortic stiffening. In additional studies, we found that blood pressure normalization by treatment with hydralazine and hydrochlorothiazide prevented angiotensin II-induced vascular T cell infiltration, aortic stiffening and collagen deposition. Finally, we found that mechanical stretch induces expression of collagen 1α1, 3α1 and 5a1 in cultured aortic fibroblasts in a p38 MAP kinase-dependent fashion, and that inhibition of p38 prevented angiotensin II-induced aortic stiffening in vivo. IL-17a also induced collagen 3a1 expression via activation of p38 MAP kinase. Conclusions Our data define a pathway in which inflammation and mechanical stretch lead to vascular inflammation that promotes collagen deposition. The resultant increase in aortic stiffness likely further worsens systolic hypertension and its attendant end-organ damage.

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Section: Discussionmentioning

confidence: 98%

Inflammation and Mechanical Stretch Promote Aortic Stiffening in Hypertension Through Activation of p38 Mitogen-Activated Protein Kinase

Thabet

Kirabo

et al. 2014

Circulation Research

214

187

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“…The phenotypic modulation from AFs to MFs participates in the neointimal formation of arteries following balloon injury [3,5,31,32], and adventitial remodeling of thickened artery wall induced by overload pressure [7,8,9,10]. Taking into consideration the similarity between AF/MF transition induced by Ang II [12,13,14] and the phenotypic transformation of AFs to MFs in injured arteries [3,5,7,8,9,10,31,32], we assume the model we used in this study to be appropriate. As we expected, α-SMA expression was increased >6-fold after Ang II treatment for 24 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Vascular adventitial fibroblasts (AFs) can be activated to transform into myofibroblasts (MFs), which proliferate and migrate into the neointima of arteries after balloon injury [3,4,5,6]. Our recent studies and those of other groups have shown that arteries are thickened under overload pressure, especially marked in adventitia, accompanied by the transformation of AFs to MFs [7,8,9,10]. MFs are characterized by the presence of α-smooth muscle actin (α-SMA) and enhanced proliferative and migratory activities.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-Mediated Overexpression of Septin 2 Attenuates α-Smooth Muscle Actin Expression and Adventitial Myofibroblast Migration Induced by Angiotensin II

Guo

Zhang²,

Wu³

et al. 2016

J Vasc Res

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Phenotypic transformation from adventitial fibroblasts (AFs) to myofibroblasts (MFs) is critical for vascular remodeling. Septin 2 was found to be downregulated during the differentiation of AFs to MFs induced by angiotensin II (Ang II); however, the role of septin 2 in this process is still unknown. In this study, we investigate whether septin 2 contributes to the adventitial MF phenotypic modulation caused by Ang II. The decreased level of septin 2 and the increased expression of α-smooth muscle actin (α-SMA), a marker of MFs, were readily observed in Ang II-stimulated MF differentiation. After gene transfer of septin 2, the expression of α-SMA was markedly decreased and the MF migration response to Ang II was inhibited. Furthermore, the inhibition of RhoA, another molecule involved in MF phenotypic modulation, decreased the motility of MFs and the expression of septin 2 triggered in Ang II. Finally, transfection of septin 2 rescued the level of acetyl-α-tubulin in MFs. These findings demonstrate that, as a downstream molecule of RhoA, septin 2 blunted the responses of AFs to Ang II by protecting α-tubulin acetylation, which suggests that septin 2 may serve as a potential therapeutic target for vascular injury.

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“…This increased structural stiffness was likely due in part to the slight, though not statistically significant, increase in wall thickness (Table 2), but it was not nearly as dramatic as that reported for humans (Zhu et al, 2006). The mutant vessels also tended to store less elastic energy upon pressurization and to dissipate more energy than the controls (Figures 2 and 3), but the latter was marked only in the ascending aorta. Diminished energy storage decreases overall aortic function, but does not necessarily imply a compromised structural integrity (Ferruzzi et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…To these numbers, we add that the overall mortality of the R247C mice with hypertension was also greater than WT (263 vs. 73 after 8 weeks of treatment), with deaths in the R247C ascribed to acute aortic dissections based on necropsy (unpublished data). It should be noted, therefore, that complementary studies in wild-type mice have not identified thoracic aortic failures in either the two-kidney, 1-clip (2K1C) model or the aortic arch banding model of hypertension (Chen et al, 2011; Kuang et al, 2013; Wagenseil et al, 2007), though chronic infusion of a high concentration of angiotensin-II can lead to dissection (Ju et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Myh11R247C/R247C mutations increase thoracic aorta vulnerability to intramural damage despite a general biomechanical adaptivity

Bellini¹,

Wang²,

Milewicz³

et al. 2015

Journal of Biomechanics

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Genetic studies in patients reveal that mutations to genes that encode contractile proteins in medial smooth muscle cells can cause thoracic aortic aneurysms and dissections. Mouse models of such mutations, including Acta2−/− and Myh11 R247C/R247C, surprisingly do not present with any severe vascular phenotype under normal conditions. This observation raises the question whether these mutations nevertheless render the thoracic aorta increasingly vulnerable to aneurysms or dissections in the presence of additional, epigenetic, factors such as hypertension, a known risk factor for thoracic aortic disease. Accordingly, we compared the structure and biaxial mechanical properties of the ascending and descending thoracic aorta from male wild-type and Myh11 R247C/R247C mice under normotension and induced hypertension. On average, the mutant aortas exhibited near normal biomechanics under normotensive hemodynamics and near normal adaptations to hypertensive hemodynamics, yet the latter led to intramural delaminations or premature deaths in over 20 percent of these mice. Moreover, the delaminated vessels exhibited localized pools of mucoid material, similar to the common histopathologic characteristic observed in aortas from humans affected by thoracic aortic aneurysms and dissections. The present findings suggest, therefore, that mutations to smooth muscle cell contractile proteins may place the thoracic aorta at increased risk to epigenetic factors and that there is a need to focus on focal, not global, changes in aortic structure and properties, including the pooling of glycosaminoglycans / proteoglycans that may lead to thoracic aortic dissection.

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Effect of an acute mechanical stimulus on aortic structure in the transverse aortic constriction mouse model

Cited by 21 publications

References 31 publications

Inflammation and Mechanical Stretch Promote Aortic Stiffening in Hypertension Through Activation of p38 Mitogen-Activated Protein Kinase

Inflammation and Mechanical Stretch Promote Aortic Stiffening in Hypertension Through Activation of p38 Mitogen-Activated Protein Kinase

Adenovirus-Mediated Overexpression of Septin 2 Attenuates α-Smooth Muscle Actin Expression and Adventitial Myofibroblast Migration Induced by Angiotensin II

Myh11R247C/R247C mutations increase thoracic aorta vulnerability to intramural damage despite a general biomechanical adaptivity

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