Elastin-insufficient mice show normal cardiovascular remodeling in 2K1C hypertension despite higher baseline pressure and unique cardiovascular architecture

Wagenseil, Jessica E.; Knutsen, Russell H.; Li, Dean Y.; Mecham, Robert P.

doi:10.1152/ajpheart.00205.2007

Cited by 25 publications

(22 citation statements)

References 34 publications

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“…The measured differences in systolic blood pressure for older mice in this study are not as dramatic as previous studies (2,8,10,23,25). Some discrepancies can be explained by differences in the anesthetic agents and methods, but it is interesting to note that the pressure differences between genotypes have decreased in the last few years in our mouse colony.…”

Section: Discussioncontrasting

confidence: 45%

Decreased aortic diameter and compliance precedes blood pressure increases in postnatal development of elastin-insufficient mice

Knutsen

Mecham

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Le VP, Knutsen RH, Mecham RP, Wagenseil JE. Decreased aortic diameter and compliance precedes blood pressure increases in postnatal development of elastin-insufficient mice. Am J Physiol Heart Circ Physiol 301: H221-H229, 2011. First published May 2, 2011; doi:10.1152/ajpheart.00119.2011.-Increased arterial stiffness and blood pressure are characteristic of humans and adult mice with reduced elastin levels caused by aging or genetic disease. Direct associations have been shown between increased arterial stiffness and hypertension in humans, but it is not known whether changes in mechanical properties or increased blood pressure occur first. Using genetically modified mice with elastin haploinsufficiency (Eln ϩ/Ϫ ), we investigated the temporal relationship between arterial mechanical properties and blood pressure throughout postnatal development. Our results show that some mechanical properties are maintained constant regardless of elastin amounts. The peak diameter compliance for both genotypes occurs near the physiologic pressure at each age, which acts to provide maximum pulse dampening. The stress-strain relationships are similar between genotypes and become nonlinear near the systolic pressure for each age, which serves to limit distension under high pressure. Our results also show that some mechanical properties are affected by reduced elastin levels and that these changes occur before measurable changes in blood pressure. Eln ϩ/Ϫ mice have decreased aortic diameter and compliance in ex vivo tests that are significant by postnatal day 7 and increased blood pressure that is not significant until postnatal day 14. This temporal relationship suggests that targeting large arteries to increase diameter or compliance may be an effective treatment for human hypertension. extracellular matrix; vasculature; vessels THE CONDUCTING ARTERIES IN vertebrates are composed of a specialized extracellular matrix (ECM) that is designed to provide elastic recoil that dampens the pulse pressure in distal arteries and reduces the work of the heart. The major ECM components are elastin and collagen, and the ratio of these proteins primarily determines the passive mechanical behavior of the large elastic arteries. Collagen is 100 -1,000 times stiffer than elastin; hence, vessels become stiffer and their elastic recoil function is compromised as the ratio of elastin to collagen is decreased (5). Arterial wall stiffness, as measured by pulse wave velocity (PWV), is independently associated with hypertension in humans and is increased even at the very early stages of the disease, suggesting that it may be a causative factor and not a resulting symptom of essential hypertension (18).Elastin amounts in humans are decreased through elastic fiber fragmentation in normal aging or through genetic mutations that affect elastin synthesis. Genetic mutations that lead to functional elastin haploinsufficiency have been linked to two inherited diseases, supravalvular aortic stenosis and Williams syndrome (7,19). The cardiovascular phenotypes of...

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Section: Discussioncontrasting

confidence: 45%

Decreased aortic diameter and compliance precedes blood pressure increases in postnatal development of elastin-insufficient mice

Knutsen

Mecham

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…In particular, similar to wild-types, the two primary changes with hypertension were a further increase in wall thickness and decrease in the in vivo value of axial stretch, both of which helped to decrease the pressureinduced increases in intramural stress toward normal values. A similar adaptation to induced hypertension has been reported for an elastin haploinsufficient mouse model (Wagenseil et al, 2007). Yet, there was an increased vulnerability to intramural delaminations by the R247C aortas in hypertension (Figure 5): only 1of10 wild-type specimens (103), but 3of15 mutant specimens (203) showed signs of intramural delamination, that is, separation of layers within the wall without frank dissection.…”

Section: Discussionsupporting

confidence: 79%

“…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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“…To our knowledge, Ldlr −/− genotype has not previously been associated with increases in systolic or pulse pressure. Eln +/− mice are known to have increased systolic and pulse pressure 19, 35 . Our blood pressure results confirm previous studies and show that Eln +/− Ldlr −/− mice on WD have the highest systolic and pulse pressure of all groups.…”

Section: Discussionmentioning

confidence: 99%

Hypertension and decreased aortic compliance due to reduced elastin amounts do not increase atherosclerotic plaque accumulation in Ldlr−/− mice

et al. 2016

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Background and Aims High blood pressure and reduced aortic compliance are associated with increased atherosclerotic plaque accumulation in humans. Animal studies support these associations, but additional factors, such as fragmented elastic fibers, are present in most previous animal studies. Elastin heterozygous (Eln+/−) mice have high blood pressure and reduced aortic compliance, with no evidence of elastic fiber fragmentation and represent an appropriate model to directly investigate the effects of these factors on atherosclerosis Methods and Results Eln+/− and Eln+/+ mice were crossed with low density lipoprotein receptor knockout (Ldlr−/−) and wild-type (Ldlr+/+) mice and fed normal or Western diet (WD) for 16 weeks. We hypothesized that on WD, Eln+/−Ldlr−/− mice with high blood pressure and reduced aortic compliance would have increased atherosclerotic plaque accumulation compared to Eln+/+Ldlr−/− mice. We measured serum cholesterol and cytokine levels, blood pressure, aortic compliance, and plaque accumulation. Contrary to our hypothesis, we found that on WD, Eln+/−Ldlr−/− mice do not have increased plaque accumulation compared to Eln+/+Ldlr−/− mice. At the aortic root, there are no significant differences in plaque area between Eln+/−Ldlr−/− and Eln+/+Ldlr−/− mice on WD (p = .89), while in the ascending aorta, Eln+/−Ldlr−/− mice on WD have 29% less normalized plaque area than Eln+/+Ldlr−/− mice on WD (p = 0.009). Conclusion Using an atherogenic mouse model, we conclude that increased blood pressure and reduced aortic compliance are not direct causes of increased aortic plaque accumulation. We propose that additional insults, such as fragmentation of elastic fibers, are necessary to alter plaque accumulation.

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Elastin-insufficient mice show normal cardiovascular remodeling in 2K1C hypertension despite higher baseline pressure and unique cardiovascular architecture

Cited by 25 publications

References 34 publications

Decreased aortic diameter and compliance precedes blood pressure increases in postnatal development of elastin-insufficient mice

Decreased aortic diameter and compliance precedes blood pressure increases in postnatal development of elastin-insufficient mice

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

Hypertension and decreased aortic compliance due to reduced elastin amounts do not increase atherosclerotic plaque accumulation in Ldlr−/− mice

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