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-induced 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.

Cardiovascular Function and Structure are Preserved Despite Induced Ablation of BMP1-Related Proteinases

“…From static mechanical tests, we observed comparable metrics of arterial stiffness in the circumferential and axial directions (Tables 2, S5). The DTA was stiffer in the circumferential compared to the axial direction as expected from previous studies 23, 45 . From dynamic mechanical tests, we observed comparable dynamic modulus and arterial damping values between the two groups (Table S5), indicating that arterial conduit and buffering functions were unimpaired due to Bmp1 and Tll1 ablation.…”

“…1) to determine overall, low-, and high-strain moduli as previously done by our group 23, 29, 42, 50 . Transition strain was taken as the intersection of the lines of best fit for the low- and high-strain regions (Fig.…”

“…Percentage of ECM proteins was calculated by dividing area marked positive for ECM proteins by the total tissue area. Collagen types I and III, which are major constituents in cardiovascular tissues, were measured using polarized light with a yellow/orange and green thresholding scheme as previously done in our group 23 . We report collagen content as the sum of type I and type III collagen values from the same sample.…”

Investigation of Pathophysiological Aspects of Aortic Growth, Remodeling, and Failure Using a Discrete-Fiber Microstructural Model

“…Pulmonary hypertension induces dilatation of the vessel [77]. This growth is marked by thickening of the media with pronounced stiffening, increase in collagen content and decrease in elastin content [78]. All of these observations are qualitatively consistent with our model and could be examined quantitatively by adjusting the model geometry and pressure loads.…”

Study of the Effect of Treatment With Atrial Natriuretic Peptide (ANP) and Cinaciguat in Chronic Hypoxic Neonatal Lambs on Residual Strain and Microstructure of the Arteries

“…In particular, uniaxial tensile test to rupture and under loading-unloading cycles were performed to determine arterial stiffness and viscoelastic properties on normoxic and hypoxic groups; from this analysis, significant differences were observed in viscoelasticity behavior, which decreased in hypoxic groups. Golob et al (2017) perform uniaxial tensile test in axial and circumferential direction in pulmonary arteries to evidence strain-and remodeling-induced stiffening by chronic pulmonary hypertension, where significant difference in high-strain stiffness modulus parameter was observed between normoxic and hypertensive groups. Wang et al (2013) by means of static and sinusoidal pressure-inflation test performed in pulmonary artery, in order to determine differences in viscoelastic behavior of chronic hypoxia-induced pulmonary hypertension and normoxic condition, concluding that static and some dynamic parameters experiment significant changes under pulmonary hypertension condition.…”