# Modeling mechano-driven and immuno-mediated aortic maladaptation in hypertension

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## Abstract

Uncontrolled hypertension is a primary risk factor for diverse cardiovascular diseases and thus remains responsible for significant morbidity and mortality. Hypertension leads to marked changes in the composition, structure, properties, and function of central arteries; hence, there has long been interest in quantifying the associated wall mechanics. Indeed, over the past 20 years there has been increasing interest in formulating mathematical models of the evolving geometry and biomechanical behavior of central arteries that occur during hypertension. In this paper, we introduce a new mathematical model of growth (changes in mass) and remodeling (changes in microstructure) of the aortic wall for an animal model of induced hypertension that exhibits both mechano-driven and immuno-mediated matrix turnover. In particular, we present a bilayered model of the aortic wall to account for differences in medial versus adventitial growth and remodeling and we include mechanical stress and inflammatory cell density as determinants of matrix turnover. Using this approach, we can capture results from a recent report of adventitial fibrosis that resulted in marked aortic maladaptation in hypertension. We submit that this model can also be used to identify novel hypotheses to guide future experimentation.

## Keywords

Aorta Central artery Stiffness Growth Remodeling Inflammation## Notes

### Acknowledgements

This work was supported, in part, by grants from the US NIH: R01 HL105297 (to C.A. Figueroa and J.D. Humphrey), U01 HL116323 (to J.D. Humphrey and G.E. Karniadakis), R01 HL128602 (to J.D. Humphrey, C.K. Breuer, and Y. Wang), P01 HL134605 (to G. Tellides and J.D. Humphrey via a PPG Award to D. Rifkin, NYU), and R03 EB021430 (to J.D. Humphrey); from the Ministerio de Educación, Cultura y Deporte of Spain: CAS17/00068 (to M. Latorre); and from Universidad Politécnica de Madrid: ‘Ayudas al personal docente e investigador para estancias breves en el extranjero 2017’ (to M. Latorre). Additional support was given to M. Latorre by grant DPI2015-69801-R from the Dirección General de Proyectos de Investigación, Ministerio de Economía y Competitividad of Spain (to F.J. Montáns and J.M. Benítez). ML gratefully acknowledges the support given by the Department of Biomedical Engineering, Yale University, during his postdoctoral stay.

### Compliance with ethical standards

### Conflict of interest

The authors declare that they have no conflict of interest.

## References

- Alford PW, Humphrey JD, Taber LA (2008) Growth and remodeling in a thick-walled artery model: effects of spatial variations in wall constituents. Biomech Model Mechanobiol 7(4):245–262CrossRefGoogle Scholar
- Baek S, Valentín A, Humphrey JD (2007) Biochemomechanics of cerebral vasospasm and its resolution: II. Constitutive relations and model simulations. Ann Biomed Eng 35(9):1498CrossRefGoogle Scholar
- Bellini C, Ferruzzi J, Roccabianca S, Di Martino ES, Humphrey JD (2014) A microstructurally motivated model of arterial wall mechanics with mechanobiological implications. Ann Biomed Eng 42(3):488–502CrossRefGoogle Scholar
- Bersi MR, Ferruzzi J, Eberth JF, Gleason RL, Humphrey JD (2014) Consistent biomechanical phenotyping of common carotid arteries from seven genetic, pharmacological, and surgical mouse models. Ann Biomed Eng 42(6):1207–1223CrossRefGoogle Scholar
- Bersi MR, Bellini C, Wu J, Montaniel KRC, Harrison DG, Humphrey JD (2016) Excessive adventitial remodeling leads to early aortic maladaptation in angiotensin-induced hypertension. Hypertension 67:890–896CrossRefGoogle Scholar
- Bersi MR, Khosravi R, Wujciak AJ, Harrison DG, Humphrey JD (2017) Differential cell-matrix mechanoadaptations and inflammation drive regional propensities to aortic fibrosis, aneurysm or dissection in hypertension. J R Soc Interface 14(136):20170,327CrossRefGoogle Scholar
- Chiquet M, Renedo AS, Huber F, Flück M (2003) How do fibroblasts translate mechanical signals into changes in extracellular matrix production? Matrix Biol 22(1):73–80CrossRefGoogle Scholar
- Davies PF (2009) Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med 6(1):16–26CrossRefGoogle Scholar
- Durrant JR, Seals DR, Connell ML, Russell MJ, Lawson BR, Folian BJ, Donato AJ, Lesniewski LA (2009) Voluntary wheel running restores endothelial function in conduit arteries of old mice: direct evidence for reduced oxidative stress, increased superoxide dismutase activity and down-regulation of NADPH oxidase. J Physiol 587(13):3271–3285CrossRefGoogle Scholar
- Eberth JF, Popovic N, Gresham VC, Wilson E, Humphrey JD (2010) Time course of carotid artery growth and remodeling in response to altered pulsatility. Am J Physiol Heart Circ Physiol 299(6):H1875–H1883CrossRefGoogle Scholar
- Figueroa CA, Baek S, Taylor CA, Humphrey JD (2009) A computational framework for fluid–solid-growth modeling in cardiovascular simulations. Comput r Methods Appl Mech Eng 198(45):3583–3602MathSciNetCrossRefGoogle Scholar
- Fridez P, Rachev A, Meister JJ, Hayashi K, Stergiopulos N (2001) Model of geometrical and smooth muscle tone adaptation of carotid artery subject to step change in pressure. Am J Physiol Heart Circ Physiol 280(6):H2752–H2760CrossRefGoogle Scholar
- Gleason RL, Humphrey JD (2004) A mixture model of arterial growth and remodeling in hypertension: altered muscle tone and tissue turnover. J Vasc Res 41(4):352–363CrossRefGoogle Scholar
- Gleason RL, Taber LA, Humphrey JD (2004) A 2-D model of flow-induced alterations in the geometry, structure, and properties of carotid arteries. J Biomech Eng 126(3):371–381CrossRefGoogle Scholar
- Haga JH, Li YSJ, Chien S (2007) Molecular basis of the effects of mechanical stretch on vascular smooth muscle cells. J Biomech 40(5):947–960CrossRefGoogle Scholar
- Hayashi K, Naiki T (2009) Adaptation and remodeling of vascular wall; biomechanical response to hypertension. J Mech Behav Biomed Mater 2(1):3–19CrossRefGoogle Scholar
- Humphrey JD (2002) Cardiovascular solid mechanics: cells, tissues and organs. Springer, BerlinCrossRefGoogle Scholar
- Humphrey JD (2008a) Mechanisms of arterial remodeling in hypertension. Hypertension 52(2):195–200CrossRefGoogle Scholar
- Humphrey JD (2008b) Vascular adaptation and mechanical homeostasis at tissue, cellular, and sub-cellular levels. Cell Biochem Biophys 50(2):53–78CrossRefGoogle Scholar
- Humphrey JD, Na S (2002) Elastodynamics and arterial wall stress. Ann Biomed Eng 30(4):509–523CrossRefGoogle Scholar
- Humphrey JD, Rajagopal KR (2002) A constrained mixture model for growth and remodeling of soft tissues. Math Models Methods Appl Sci 12(03):407–430MathSciNetCrossRefGoogle Scholar
- Humphrey JD, Dufresne ER, Schwartz MA (2014) Mechanotransduction and extracellular matrix homeostasis. Nat Rev Mol Cell Biol 15(12):802–812CrossRefGoogle Scholar
- Latorre M, Humphrey JD (2018) Critical roles of time-scales in soft tissue growth and remodeling. APL Bioeng 2(2):026108CrossRefGoogle Scholar
- Latorre M, De Rosa E, Montáns FJ (2017) Understanding the need of the compression branch to characterize hyperelastic materials. Int J Non-linear Mech 89:14–24CrossRefGoogle Scholar
- Lesniewski LA, Durrant JR, Connell ML, Henson GD, Black AD, Donato AJ, Seals DR (2011) Aerobic exercise reverses arterial inflammation with aging in mice. Am J Physiol Heart Circ Physiol 301(3):H1025–H1032CrossRefGoogle Scholar
- Miller KS, Lee YU, Naito Y, Breuer CK, Humphrey JD (2014) Computational model of the in vivo development of a tissue engineered vein from an implanted polymeric construct. J Biomech 47(9):2080–2087CrossRefGoogle Scholar
- Nissen R, Cardinale GJ, Udenfriend S (1978) Increased turnover of arterial collagen in hypertensive rats. Proc Natl Acad Sci 75(1):451–453CrossRefGoogle Scholar
- Rachev A, Gleason RL (2011) Theoretical study on the effects of pressure-induced remodeling on geometry and mechanical non-homogeneity of conduit arteries. Biomech Model Mechanobiol 10(1):79–93CrossRefGoogle Scholar
- Rachev A, Stergiopulos N, Meister JJ (1996) Theoretical study of dynamics of arterial wall remodeling in response to changes in blood pressure. J Biomech 29(5):635–642CrossRefGoogle Scholar
- Rachev A, Taylor WR, Vito RP (2013) Calculation of the outcomes of remodeling of arteries subjected to sustained hypertension using a 3D two-layered model. Ann Biomed Eng 41(7):1539–1553CrossRefGoogle Scholar
- Rezakhaniha R, Fonck E, Genoud C, Stergiopulos N (2011) Role of elastin anisotropy in structural strain energy functions of arterial tissue. Biomech Model Mechanobiol 10(4):599–611CrossRefGoogle Scholar
- Taber LA, Eggers DW (1996) Theoretical study of stress-modulated growth in the aorta. J Theor Biol 180(4):343–357CrossRefGoogle Scholar
- Tellides G, Pober JS (2015) Inflammatory and immune responses in the arterial media. Circ Res 116(2):312–322CrossRefGoogle Scholar
- Tsamis A, Stergiopulos N, Rachev A (2009) A structure-based model of arterial remodeling in response to sustained hypertension. J Biomech Eng 131(10):101,004CrossRefGoogle Scholar
- Valentín A, Humphrey JD (2009) Evaluation of fundamental hypotheses underlying constrained mixture models of arterial growth and remodelling. Philos Trans R Soc Lond A Math Phys Eng Sci 367(1902):3585–3606MathSciNetCrossRefGoogle Scholar
- Valentín A, Cardamone L, Baek S, Humphrey JD (2009) Complementary vasoactivity and matrix remodelling in arterial adaptations to altered flow and pressure. J R Soc Interface 6(32):293–306CrossRefGoogle Scholar
- Wilson JS, Baek S, Humphrey JD (2012) Importance of initial aortic properties on the evolving regional anisotropy, stiffness and wall thickness of human abdominal aortic aneurysms. J R Soc Interface 9(74):2047–58CrossRefGoogle Scholar
- Wu J, Thabet SR, Kirabo A, Trott DW, Saleh MA, Xiao L, Madhur MS, Chen W, Harrison DG (2014) Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ Res 114:616–625CrossRefGoogle Scholar
- Wu J, Saleh MA, Kirabo A, Itani HA, Montaniel KRC, Xiao L, Chen W, Mernaugh RL, Cai H, Bernstein KE, Goronzy JJ, Weyand CM, Curci JA, Barbaro NR, Moreno H, Davies SS, Roberts LJ, Madhur MS, Harrison DG (2016) Immune activation caused by vascular oxidation promotes fibrosis and hypertension. J Clin Investig 126(1):50–67CrossRefGoogle Scholar