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Research Papers

MMP12 Deletion Preferentially Attenuates Axial Stiffening of Aging Arteries

[+] Author and Article Information
Sonja A. Brankovic, Elizabeth A. Hawthorne

Center for Engineering MechanoBiology,
Department of Systems Pharmacology
and Translational Therapeutics,
University of Pennsylvania,
Philadelphia, PA 19104

Xunjie Yu

Department of Mechanical Engineering,
Boston University,
Boston, MA 02215

Yanhang Zhang

Department of Mechanical Engineering,
Boston University,
Boston, MA 02215;
Department of Biomedical Engineering,
Boston University,
Boston, MA 02215

Richard K. Assoian

Center for Engineering MechanoBiology,
Department of Systems Pharmacology
and Translational Therapeutics,
University of Pennsylvania,
Philadelphia, PA 19104
e-mail: assoian@pennmedicine.upenn.edu

1Corresponding author.

Manuscript received July 5, 2018; final manuscript received March 6, 2019; published online May 6, 2019. Assoc. Editor: Jonathan Vande Geest.

J Biomech Eng 141(8), 081004 (May 06, 2019) (9 pages) Paper No: BIO-18-1313; doi: 10.1115/1.4043322 History: Received July 05, 2018; Revised March 06, 2019

Arterial stiffening is a hallmark of aging, but how aging affects the arterial response to pressure is still not completely understood, especially with regard to specific matrix metalloproteinases (MMPs). Here, we performed biaxial inflation–extension tests on C57BL/6 mice to study the effects of age and MMP12, a major arterial elastase, on arterial biomechanics. Aging from 2 to 24 months leads to both circumferential and axial stiffening with stretch, and these changes are associated with an increased wall thickness, a decreased inner radius–wall thickness ratio, and a decreased in vivo axial stretch. Analysis of in vivo stretch and stress–stretch curves with arteries from age- and sex-matched wild-type (WT) and MMP12-null arteries demonstrates that MMP12 deletion attenuates age-dependent arterial stiffening, mostly in the axial direction. MMP12 deletion also prevents the aging-associated decrease in the in vivo stretch and, in general, leads to an axial mechanics phenotype characteristic of much younger mice. Circumferential arterial mechanics were much less affected by deletion of MMP12. We conclude that the induction of MMP12 during aging preferentially promotes axial arterial stiffening.

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References

Sutton-Tyrrell, K. , Najjar, S. S. , Boudreau, R. M. , Venkitachalam, L. , Kupelian, V. , Simonsick, E. M. , Havlik, R. , Lakatta, E. G. , Spurgeon, H. , Kritchevsky, S. , Pahor, M. , Bauer, D. , and Newman, A. , 2005, “ Elevated Aortic Pulse Wave Velocity, a Marker of Arterial Stiffness, Predicts Cardiovascular Events in Well-Functioning Older Adults,” Circulation, 111(25), pp. 3384–3390. [CrossRef] [PubMed]
Boutouyrie, P. , Tropeano, A. I. , Asmar, R. , Gautier, I. , Benetos, A. , Lacolley, P. , and Laurent, S. , 2002, “ Aortic Stiffness Is an Independent Predictor of Primary Coronary Events in Hypertensive Patients,” Hypertension, 39(1), p. 10. [CrossRef] [PubMed]
Wilson, P. W. F. , D'Agostino, R. B. , Levy, D. , Belanger, A. M. , Silbershatz, H. , and Kannel, W. B. , 1998, “ Prediction of Coronary Heart Disease Using Risk Factor Categories,” Circulation, 97(18), p. 1837. [CrossRef] [PubMed]
Wagenseil, J. E. , and Mecham, R. P. , 2009, “ Vascular Extracellular Matrix and Arterial Mechanics,” Physiol. Rev., 89(3), pp. 957–989. [CrossRef] [PubMed]
Lindeman, J. H. N. , Ashcroft, B. A. , Beenakker, J.-W. M. , van Es, M. , Koekkoek, N. B. R. , Prins, F. A. , Tielemans, J. F. , Abdul-Hussien, H. , Bank, R. A. , and Oosterkamp, T. H. , 2010, “ Distinct Defects in Collagen Microarchitecture Underlie Vessel-Wall Failure in Advanced Abdominal Aneurysms and Aneurysms in Marfan Syndrome,” Proc. Natl. Acad. Sci. U. S. A., 107(2), pp. 862–865. [CrossRef] [PubMed]
VanBavel, E. , Siersma, P. , and Spaan, J. A. E. , 2003, “ Elasticity of Passive Blood Vessels: A New Concept,” Am. J. Physiol. Circ. Physiol., 285(5), pp. H1986–H2000. [CrossRef]
Armentano, R. L. , Barra, J. G. , Levenson, J. , Simon, A. , and Pichel, R. H. , 1995, “ Arterial Wall Mechanics in Conscious Dogs,” Circ. Res., 76(3), p. 468. [CrossRef] [PubMed]
Green, E. M. , Mansfield, J. C. , Bell, J. S. , and Winlove, C. P. , 2014, “ The Structure and Micromechanics of Elastic Tissue,” Interface Focus, 4(2), p. 20130058. [CrossRef] [PubMed]
Greenwald, S. E. , 2007, “ Ageing of the Conduit Arteries,” J. Pathol., 211(2), pp. 157–172. [CrossRef] [PubMed]
Harvey, A. , Montezano, A. C. , and Touyz, R. M. , 2015, “ Vascular Biology of Ageing—Implications in Hypertension,” J. Mol. Cell. Cardiol., 83, pp. 112–121. [CrossRef] [PubMed]
Zieman, S. J. , Melenovsky, V. , and Kass, D. A. , 2005, “ Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness,” Arterioscler., Thromb., Vasc. Biol., 25(5), pp. 932–943. [CrossRef]
Cox, R. H. , 1983, “ Age-Related Changes in Arterial Wall Mechanics and Composition of NIA Fischer Rats,” Mech. Ageing Dev., 23(1), pp. 21–36. [CrossRef] [PubMed]
Mandala, M. , Pedatella, A. L. , Morales Palomares, S. , Cipolla, M. J. , and Osol, G. , 2012, “ Maturation is Associated With Changes in Rat Cerebral Artery Structure, Biomechanical Properties and Tone,” Acta Physiol., 205(3), pp. 363–371. [CrossRef]
Gaballa, M. A. , Jacob, C. T. , Raya, T. E. , Liu, J. , Simon, B. , and Goldman, S. , 1998, “ Large Artery Remodeling During Aging,” Hypertension, 32(3), pp. 437–443. [CrossRef] [PubMed]
Diaz-Otero, J. M. , Garver, H. , Fink, G. D. , Jackson, W. F. , and Dorrance, A. M. , 2016, “ Aging is Associated With Changes to the Biomechanical Properties of the Posterior Cerebral Artery and Parenchymal Arterioles,” Am. J. Physiol.: Hear. Circ. Physiol., 310(3), pp. H365–H375. [CrossRef]
Ferruzzi, J. , Madziva, D. , Caulk, A. W. , Tellides, G. , and Humphrey, J. D. , 2018, “ Compromised Mechanical Homeostasis in Arterial Aging and Associated Cardiovascular Consequences,” Biomech. Model. Mechanobiol., 17(5), pp. 1281–1295. [CrossRef] [PubMed]
Mithieux, S. M. , and Weiss, A. S. , 2005, “ Elastin,” Adv. Protein Chem., 70, pp. 437–461. [CrossRef] [PubMed]
Sherratt, M. J. , 2009, “ Tissue Elasticity and the Ageing Elastic Fibre,” Age., 31(4), pp. 305–325. [CrossRef]
Werb, Z. , Banda, M. J. , and Jones, P. A. , 1980, “ Degradation of Connective Tissue Matrices by Macrophages. I. Proteolysis of Elastin, Glycoproteins, and Collagen by Proteinases Isolated From Macrophages,” J. Exp. Med., 152(5), pp. 1340–1357. [CrossRef] [PubMed]
Banda, M. J. , and Werb, Z. , 1981, “ Mouse Macrophage Elastase. Purification and Characterization as a Metalloproteinase,” Biochem. J., 193(2), pp. 589–605. [CrossRef] [PubMed]
Liu, S.-L. , Bae, Y. H. , Yu, C. , Monslow, J. , Hawthorne, E. A. , Castagnino, P. , Branchetti, E. , Ferrari, G. , Damrauer, S. M. , Puré, E. , and Assoian, R. K. , 2015, “ Matrix Metalloproteinase-12 is an Essential Mediator of Acute and Chronic Arterial Stiffening,” Sci. Rep., 5, p. 17189. [CrossRef] [PubMed]
Gosline, J. , Lillie, M. , Carrington, E. , Guerette, P. , Ortlepp, C. , and Savage, K. , 2002, “ Elastic Proteins: Biological Roles and Mechanical Properties,” Philos. Trans. R. Soc. London, Ser. B, 357(1418), pp. 121–132. [CrossRef]
Shirwany, N. A. , and Zou, M. , 2010, “ Arterial Stiffness: A Brief Review,” Acta Pharmacol. Sin., 31(10), pp. 1267–1276. [CrossRef] [PubMed]
Ferruzzi, J. , Bersi, M. R. , and Humphrey, J. D. , 2013, “ Biomechanical Phenotyping of Central Arteries in Health and Disease: Advantages of and Methods for Murine Models,” Ann. Biomed. Eng., 41(7), pp. 1311–1330. [CrossRef] [PubMed]
Weizsacker, H. W. , Lambert, H. , and Pascale, K. , 1983, “ Analysis of the Passive Mechanical Properties of Rat Carotid Arteries,” J. Biomech., 16(9), pp. 703–715. [CrossRef] [PubMed]
Humphrey, J. D. , Eberth, J. F. , Dye, W. W. , and Gleason, R. L. , 2009, “ Fundamental Role of Axial Stress in Compensatory Adaptations by Arteries,” J. Biomech., 42(1), pp. 1–8. [CrossRef] [PubMed]
Mirsky, I. , and Parmley, W. W. , 1973, “ Assessment of Passive Elastic Stiffness for Isolated Heart Muscle and the Intact Heart,” Circ. Res., 33(2), pp. 233–243. [CrossRef] [PubMed]
Horny, L. , Adamek, T. , and Zitny, R. , 2013, “ Age-Related Changes in Longitudinal Prestress Related Changes in Longitudinal Prestress Related Changes in Longitudinal Prestress in Human Abdominal Aorta,” Arch. Appl. Mech., 83(6), pp. 875–888. [CrossRef]
Cuomo, F. , Roccabianca, S. , Dillon-Murphy, D. , Xiao, N. , Humphrey, J. D. , and Figueroa, C. A. , 2017, “ Effects of Age-Associated Regional Changes in Aortic Stiffness on Human Hemodynamics Revealed by Computational Modeling,” PLoS One, 12(3), p. e0173177. [CrossRef] [PubMed]
Liu, S.-L. , Bae, Y. H. , Yu, C. , Monslow, J. , Hawthorne, E. A. , Castagnino, P. , Branchetti, E. , Ferrari, G. , Damrauer, S. M. , Puré, E. , and Assoian, R. K. , 2015, “ Matrix Metalloproteinase-12 is an Essential Mediator of Acute and Chronic Arterial Stiffening,” Sci. Rep., 5, p. 17189.
Davis, E. C. , 1993, “ Stability of Elastin in the Developing Mouse Aorta: A Quantitative Radioautographic Study,” Histochemistry, 100(1), pp. 17–26. [CrossRef] [PubMed]
Humphrey, J. D. , Dufresne, E. R. , and Schwartz, M. A. , 2014, “ Mechanotransduction and Extracellular Matrix Homeostasis,” Nat. Rev. Mol. Cell Biol., 15(12), pp. 802–812. [CrossRef] [PubMed]
Chow, M. J. , Turcotte, R. , Lin, C. P. , and Zhang, Y. , 2014, “ Arterial Extracellular Matrix: A Mechanobiological Study of the Contributions and Interactions of Elastin and Collagen,” Biophys. J., 106(12), pp. 2684–2692.
Kohn, J. C. , Lampi, M. C. , and Reinhart-King, C. A. , 2015, “ Age-Related Vascular Stiffening: Causes and Consequences,” Front. Genet., 6, p. 112.
Wagenseil, J. E. , Nerurkar, N. L. , Knutsen, R. H. , Okamoto, R. J. , Li, D. Y. , and Mecham, R. P. , 2005, “ Effects of Elastin Haploinsufficiency on the Mechanical Behavior of Mouse Arteries,” Am. J. Physiol. Hear. Circ. Physiol., 289(3), pp. H1209–H1217. [CrossRef]
Ferruzzi, J. , Bersi, M. R. , Mecham, R. P. , Ramirez, F. , Yanagisawa, H. , Tellides, G. , and Humphrey, J. D. , 2016, “ Loss of Elastic Fiber Integrity Compromises Common Carotid Artery Function: Implications for Vascular Aging,” Artery Res., 14, pp. 41–52. [CrossRef] [PubMed]
Carta, L. , Wagenseil, J. E. , Knutsen, R. H. , Mariko, B. , Faury, G. , Davis, E. C. , Starcher, B. , Mecham, R. P. , and Ramirez, F. , 2009, “ Discrete Contributions of Elastic Fiber Components to Arterial Development and Mechanical Compliance,” Arterioscler., Thromb. Vasc. Biol., 29(12), p. 2083. [CrossRef]
Chow, M. J. , Mondonedo, J. R. , Johnson, V. M. , and Zhang, Y. , 2013, “ Progressive Structural and Biomechanical Changes in Elastin Degraded Aorta,” Biomech. Model. Mechanobiol., 12(2), pp. 361–372. [CrossRef] [PubMed]
Collins, M. J. , Eberth, J. F. , Wilson, E. , and Humphrey, J. D. , 2012, “ Acute Mechanical Effects of Elastase on the Infrarenal Mouse Aorta: Implications for Models of Aneurysms,” J. Biomech., 45(4), pp. 660–665. [CrossRef] [PubMed]
Dobrin, P. B. , and Canfield, T. R. , 1984, “ Elastase, Collagenase, and the Biaxial Elastic Properties of Dog Carotid Artery,” Am. J. Physiol., 247(1 Pt. 2), pp. H124–H131. [PubMed]
Farand, P. , Garon, A. , and Plante, G. E. , 2007, “ Structure of Large Arteries: Orientation of Elastin in Rabbit Aortic Internal Elastic Lamina and in the Elastic Lamellae of Aortic Media,” Microvasc. Res., 73(2), pp. 95–99. [CrossRef] [PubMed]
Yu, X. , Wang, Y. , and Zhang, Y. , 2018, “ Transmural Variation in Elastin Fiber Orientation Distribution in the Arterial Wall,” J. Mech. Behav. Biomed. Mater., 77, pp. 745–753.
Gronski , T. J., Jr. , Martin, R. L. , Kobayashi, D. K. , Walsh, B. C. , Holman, M. C. , Huber, M. , Van Wart, H. E. , and Shapiro, S. D. , 1997, “ Hydrolysis of a Broad Spectrum of Extracellular Matrix Proteins by Human Macrophage Elastase,” J. Biol. Chem., 272(18), pp. 12189–12194. [CrossRef] [PubMed]
Wells, J. M. , Gaggar, A. , and Blalock, J. E. , 2015, “ MMP Generated Matrikines,” Matrix Biol., 44–46, pp. 122–129. [CrossRef] [PubMed]
Marchant, D. J. , Bellac, C. L. , Moraes, T. J. , Wadsworth, S. J. , Dufour, A. , Butler, G. S. , Bilawchuk, L. M. , Hendry, R. G. , Robertson, A. G. , Cheung, C. T. , Ng, J. , Ang, L. , Luo, Z. , Heilbron, K. , Norris, M. J. , Duan, W. , Bucyk, T. , Karpov, A. , Devel, L. , Georgiadis, D. , Hegele, R. G. , Luo, H. , Granville, D. J. , Dive, V. , McManus, B. M. , and Overall, C. M. , 2014, “ A New Transcriptional Role for Matrix Metalloproteinase-12 in Antiviral Immunity,” Nat. Med., 20(5), pp. 493–502. [CrossRef] [PubMed]
Soler, A. , Hunter, I. , Joseph, G. , Hutcheson, R. , Hutcheson, B. , Yang, J. , Zhang, F. F. , Joshi, S. R. , Bradford, C. , Gotlinger, K. H. , Maniyar, R. , Falck, J. R. , Proctor, S. , Schwartzman, M. L. , Gupte, S. A. , and Rocic, P. , 2018, “ Elevated 20-HETE in Metabolic Syndrome Regulates Arterial Stiffness and Systolic Hypertension Via MMP12 Activation,” J. Mol. Cell. Cardiol., 117, pp. 88–99. [CrossRef] [PubMed]

Figures

Grahic Jump Location
Fig. 1

Vessel wall remodeling of WT and MMP12-null mice. ((a) and (d)) Loaded vessel wall thickness and ((b) and (e)) inner (lumen) radius of male WT (2 month, n = 7; 6 month, n = 5; 12 month, n = 7; 24 month, n = 5) and MMP12-null (12 month, n = 7; 24 month, n = 6) carotid arteries as described in Methods. ((c) and (f)) show the ratios of inner radius to wall thickness. Data show mean ± SEM. All data were analyzed by ANOVA. See Methods for statistical tests and definitions of asterisks. Results from the same 12- and 24-month WT arteries are shown in all panels for comparison.

Grahic Jump Location
Fig. 2

Axial arterial mechanics of aging WT and MMP12-null mice. Axial arterial mechanics of carotid arteries from male WT (2 month, n = 7; 6 month, n = 5; 12 month, n = 7; 24 month, n = 5) and MMP12-null (12 month, n = 7; 24 month, n = 6) mice were tested using pressure myography as described in Methods. (a) Axial stress–stretch curves of the WT aging carotids were determined at 90 mm Hg. (b) Axial stress–stretch curves of the age-matched MMP12-null and WT carotid arteries were determined at 90 mm Hg. Results in all panels show mean ± SD. ((c) and (d)) Corresponding axial force–stretch curves. All data were analyzed by ANOVA. See Methods for statistical tests and definitions of asterisks. Results from the same 12- and 24-month WT arteries are shown in all panels for comparison.

Grahic Jump Location
Fig. 3

Circumferential arterial mechanics of aging WT and MMP12-null mice. (a) Pressure–outer diameter and (b) circumferential stress–stretch curves of aging WT carotid arteries (2 month, n = 7; 6 month, n = 5; 12 month, n = 7; 24 month, n = 5) as determined by pressure myography (see Methods). Statistical differences in panel A refer to the 2-month versus 24 month WT arteries. Statistical differences in panel B depended on the pressure, p-values for stresses ranged from <0.05 to <0.001 for the 12-month tissues and <0.01 to <0.0001 for the 24-month tissues in the physiological range of 80–120 mm Hg. The largest p-value is shown for simplicity of presentation. (c) Pressure–outer diameter and (d) circumferential stress–stretch curves of 24-month age-matched MMP12-null (n = 6) and WT (n = 5) carotid arteries were determined as described in Methods. Red symbols in B and D indicate the results obtained at 80–120 mm Hg. Results show mean ± SEM. All data were analyzed by ANOVA. See Methods for use of statistical tests and definitions of asterisks. Results from the same 24-month WT arteries are shown in all panels for comparison.

Grahic Jump Location
Fig. 4

MMP12 increases axial stress in aging murine carotid arteries. (a) The IVS of carotid arteries from male WT (2 month, n = 7; 6 month, n = 5; 12 month, n = 7; 24 month, n = 5) and MMP12-null (12 month, n = 7; 24 month, n = 6) mice were determined by axial force–length tests as described in Methods. Results show mean ± SD. ANOVAs were used to analyze the effect of WT aging, and Mann–Whitney tests were used to analyze the effect of MMP12 deletion at fixed ages of 12 or 24 months. (b) The axial stresses of the carotid arteries from the 2-month WT mice, 24-month WT mice, and 24-month MMP12-null mice were determined at the mean stretches of the 2-, 6-, 12-, and 24-month WT mice (1.967, 1.864, 1.765, and 1.729, respectively; see (a)). Black arrows indicate the average IVS for each group, and the shaded horizontal bar represents the mean axial stress ± SD at each artery's age-adjusted IVS. Statistical significance was determined by ANOVA for each condition. (c) The axial stresses of individual carotid arteries from 24-month WT mice and 24-month MMP12-null mice were determined at the respective IVS; statistical significance was determined using Mann–Whitney tests. The results in panels B and C are shown as box and whisker plots with Tukey whiskers and the horizontal lines of boxes representing the 25th percentile, the median, and the 75% percentile. See Methods for use of statistical tests and definitions of asterisks.

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