title: Pulmonary arterial strain- and remodeling-induced stiffening are differentiated in a chronic model of pulmonary hypertension.
abstract: Pulmonary hypertension (PH) is a debilitating vascular disease that leads to pulmonary artery (PA) stiffening, which is a predictor of patient mortality. During PH development, PA stiffening adversely affects right ventricular function. PA stiffening has been investigated through the arterial nonlinear elastic response during mechanical testing using a canine PH model. However, only circumferential properties were reported and in the absence of chronic PH-induced PA remodeling. Remodeling can alter arterial nonlinear elastic properties via chronic changes in extracellular matrix (ECM) content and geometry. Here, we used an established constitutive model to demonstrate and differentiate between strain-stiffening, which is due to nonlinear elasticity, and remodeling-induced stiffening, which is due to ECM and geometric changes, in a canine model of chronic thromboembolic PH (CTEPH). To do this, circumferential and axial tissue strips of large extralobar PAs from control and CTEPH tissues were tested in uniaxial tension, and data were fit to a phenomenological constitutive model. Strain-induced stiffening was evident from mechanical testing as nonlinear elasticity in both directions and computationally by a high correlation coefficient between the mechanical data and model (R2=0.89). Remodeling-induced stiffening was evident from a significant increase in the constitutive model stress parameter, which correlated with increased PA collagen content and decreased PA elastin content as measured histologically. The ability to differentiate between strain- and remodeling-induced stiffening in vivo may lead to tailored clinical treatments for PA stiffening in PH patients.
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering, Madison, WI 53706, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Golob
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering, Madison, WI 53706, United States.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Tabima
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering, Madison, WI 53706, United States.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Wolf
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering, Madison, WI 53706, United States.
authors.forename: James L
authors.initials: JL
authors.lastname: Johnston
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering, Madison, WI 53706, United States.
authors.forename: Omid
authors.initials: O
authors.lastname: Forouzan
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering, Madison, WI 53706, United States.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Mulchrone
authors.affiliation: Department of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, United States.
authors.forename: Heidi B
authors.initials: HB
authors.lastname: Kellihan
authors.affiliation: Department of Physiology, University of Iowa, Iowa City, IA 52242, United States.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Bates
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering, Madison, WI 53706, United States. Electronic address: Naomi.Chesler@wisc.edu.
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Chesler
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004548:Elasticity; D005109:Extracellular Matrix / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology*; D013314:Stress, Mechanical; D066253:Vascular Remodeling
chemical_list: D003094:Collagen
keywords: Collagen; Constitutive model; Elastic modulus; Pulmonary embolization