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Research Papers

Effects of Increased Arterial Stiffness on Atherosclerotic Plaque Amounts

[+] Author and Article Information
Kellie V. Stoka, Justine A. Maedeker, Jesse D. Procknow

Department of Mechanical Engineering
and Materials Science,
Washington University,
St. Louis, MO 63130

Lisa Bennett, Siddharth A. Bhayani, William S. Gardner

Department of Biomedical Engineering,
Saint Louis University,
St. Louis, MO 63130

Austin J. Cocciolone

Department of Mechanical Engineering
and Materials Science,
Washington University,
One Brookings Dr., CB 1185,
St. Louis, MO 63130

Tezin A. Walji, Clarissa S. Craft

Department of Cell Biology and Physiology,
Washington University,
St. Louis, MO 63130

Jessica E. Wagenseil

Department of Mechanical Engineering
and Materials Science,
Washington University,
One Brookings Dr., CB 1185,
St. Louis, MO 63130
e-mail: jessica.wagenseil@wustl.edu

1Corresponding author.

Manuscript received October 27, 2017; final manuscript received January 4, 2018; published online March 5, 2018. Assoc. Editor: Raffaella De Vita.

J Biomech Eng 140(5), 051007 (Mar 05, 2018) (10 pages) Paper No: BIO-17-1488; doi: 10.1115/1.4039175 History: Received October 27, 2017; Revised January 04, 2018

Increased arterial stiffness is associated with atherosclerosis in humans, but there have been limited animal studies investigating the relationship between these factors. We bred elastin wildtype (Eln+/+) and heterozygous (Eln+/−) mice to apolipoprotein E wildtype (Apoe+/+) and knockout (Apoe−/−) mice and fed them normal diet (ND) or Western diet (WD) for 12 weeks. Eln+/− mice have increased arterial stiffness. Apoe−/− mice develop atherosclerosis on ND that is accelerated by WD. It has been reported that Apoe−/− mice have increased arterial stiffness and that the increased stiffness may play a role in atherosclerotic plaque progression. We found that Eln+/+Apoe−/− arterial stiffness is similar to Eln+/+Apoe+/+ mice at physiologic pressures, suggesting that changes in stiffness do not play a role in atherosclerotic plaque progression in Apoe−/− mice. We found that Eln+/−Apoe−/− mice have increased structural arterial stiffness compared to Eln+/+Apoe−/− mice, but they only have increased amounts of ascending aortic plaque on ND, not WD. The results suggest a change in atherosclerosis progression but not end stage disease in Eln+/−Apoe−/− mice due to increased arterial stiffness. Possible contributing factors include increased blood pressure and changes in circulating levels of interleukin-6 (IL6) and transforming growth factor beta 1 (TGF-β1) that are also associated with Eln+/− genotype.

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Figures

Grahic Jump Location
Fig. 1

In vivo axial stretch ratios (a) were measured by imaging the carotid artery before and after dissection. Individual measurements are shown with mean±SD. P values are from one-way ANOVA for Eln genotype. Mean carotid artery pressure-diameter curves from in vitro mechanical tests are shown for mice on ND (b) or WD (c) for 12 weeks after weaning. Significant effect of *Eln genotype or #Apoe genotype by three-way ANOVA.

Grahic Jump Location
Fig. 2

Inner and outer carotid artery boundaries were traced on images of H&E stained sections to obtain unloaded dimensions. Representative sections for four of the eight groups are shown in (a). Scale bars = 50 μm. Eln+/− arteries have smaller unloaded diameters (b) and thicknesses (c). P values are from one-way ANOVA for Eln genotype. Results for three-way ANOVA are given in the text. Individual measurements are shown with mean±SD.

Grahic Jump Location
Fig. 3

Circumferential Cauchy stress-stretch relationships for the carotid arteries were calculated from the pressure-diameter behavior and the unloaded dimensions for each group on ND (a) and WD (b). Mean±SD.

Grahic Jump Location
Fig. 4

Physiologic values of the systolic circumferential Cauchy stress (a), systolic circumferential stretch (b), structural stiffness (Ep) (c), and material stiffness (Einc) (d) for the carotid artery were calculated using the mechanical test data and measured blood pressures. P values are from one-way ANOVA for Eln genotype. Results for three-way ANOVA are given in the text. Overall, Eln+/ carotid arteries have smaller systolic circumferential Cauchy stresses and larger Ep than Eln+/+. Individual measurements are shown with mean±SD.

Grahic Jump Location
Fig. 5

Representative carotid artery sections stained with VVG (top) and PSR (bottom) for groups on WD. VVG stains elastic fibers black, muscle brown, and collagen pink. PSR stains collagen red on a pale yellow background. (Please refer to online article for color figures.) Note the additional layer of elastic fibers in Eln+/− VVG images (white arrows) and the clear outline of collagen fibers around the elastic fibers in Eln+/+ PSR images (black arrows). Scale bars = 10 μm.

Grahic Jump Location
Fig. 6

Quantification of total plaque area at the aortic root (a). P value is from one-way ANOVA for Eln genotype. Results for three-way ANOVA are given in the text. Individual measurements are shown with mean±SD. Representative images of Apoe−/− aortic root sections stained with oil red O are shown in panels (b)–(e).

Grahic Jump Location
Fig. 7

Quantification of the percentage of the ascending aorta lumen area covered in plaque (a). P value is from one-way ANOVA for Eln genotype. Results for three-way ANOVA are given in the text. Individual measurements are shown with mean±SD. Representative images of Apoe−/− ascending aorta en face preparations stained with oil red O are shown in panels (b)–(e).

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