title: Validation of an arterial constitutive model accounting for collagen content and crosslinking.
abstract: During the progression of pulmonary hypertension (PH), proximal pulmonary arteries (PAs) increase in both thickness and stiffness. Collagen, a component of the extracellular matrix, is mainly responsible for these changes via increased collagen fiber amount (or content) and crosslinking. We sought to differentiate the effects of collagen content and cross-linking on mouse PA mechanical changes using a constitutive model with parameters derived from experiments in which collagen content and cross-linking were decoupled during hypoxic pulmonary hypertension (HPH). We employed an eight-chain orthotropic element model to characterize collagen's mechanical behavior and an isotropic neo-Hookean form to represent elastin. Our results showed a strong correlation between the material parameter related to collagen content and measured collagen content (R(2)=0.82, P<0.0001) and a moderate correlation between the material parameter related to collagen crosslinking and measured crosslinking (R(2)=0.24, P=0.06). There was no significant change in either the material parameter related to elastin or the measured elastin content from histology. The model-predicted pressure at which collagen begins to engage was ∼25mmHg, which is consistent with experimental observations. We conclude that this model may allow us to predict changes in the arterial extracellular matrix from measured mechanical behavior in PH patients, which may provide insight into prognoses and the effects of therapy.
  
  
  CONCLUSIONS
  The literature has proposed several constitutive models to describe the mechanical effects of arterial collagen but none separates collagen content from crosslinking. Given that both are critical to arterial mechanics, the novel model described here does so. Furthermore, our novel model is well tested by experimental data; model parameters were reasonably correlated with measured collagen content and crosslinking and the model-predicted collagen transition stretch was consistent with that obtained experimentally. Given that arterial collagen structural changes and collagen engagement are critical to arterial stiffening in several disease states, this model, by linking mechanical and biological properties, may allow us to predict important biological changes during disease progression from measured mechanical behavior.
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Lian
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Eickhoff
authors.affiliation: Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA. Electronic address: chesler@engr.wisc.edu.
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Chesler
mesh_terms: D000629:Aminopropionitrile / Q000737:chemistry; D000818:Animals; D003094:Collagen / Q000737:chemistry*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004548:Elasticity; D004549:Elastin / Q000737:chemistry; D005109:Extracellular Matrix / Q000378:metabolism; D006909:Hydroxyproline / Q000737:chemistry; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D000860:Hypoxia; D008422:Materials Testing; D051379:Mice; D008953:Models, Anatomic; D009154:Mutation; D011312:Pressure; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D013314:Stress, Mechanical
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D000629:Aminopropionitrile; D003094:Collagen; D004549:Elastin; D006909:Hydroxyproline
keywords: Hydroxyproline; Large pulmonary artery; Modeling; Pyridinoline; β-Aminopropionitrile (BAPN)