Extracellular matrix remodeling has been proposed as one mechanism by which proximal pulmonary arteries stiffen during pulmonary arterial hypertension (PAH). Although some attention has been paid to the role of collagen and metallomatrix proteins in affecting vascular stiffness, much less work has been performed on changes in elastin structure-function relationships in PAH. Such work is warranted, given the importance of elastin as the structural protein primarily responsible for the passive elastic behavior of these conduit arteries. Here, we study structure-function relationships of fresh arterial tissue and purified arterial elastin from the main, left, and right pulmonary artery branches of normotensive and hypoxia-induced pulmonary hypertensive neonatal calves. PAH resulted in an average 81 and 72% increase in stiffness of fresh and digested tissue, respectively. Increase in stiffness appears most attributable to elevated elastic modulus, which increased 46 and 65%, respectively, for fresh and digested tissue. Comparison between fresh and digested tissues shows that, at 35% strain, a minimum of 48% of the arterial load is carried by elastin, and a minimum of 43% of the change in stiffness of arterial tissue is due to the change in elastin stiffness. Analysis of the stress-strain behavior revealed that PAH causes an increase in the strains associated with the physiological pressure range but had no effect on the strain of transition from elastin-dominant to collagen-dominant behavior. These results indicate that mechanobiological adaptations of the continuum and geometric properties of elastin, in response to PAH, significantly elevate the circumferential stiffness of proximal pulmonary arterial tissue.

No abstract

In pulmonary arteries (PA), mechanical function is largely driven by the underlying microstructure of the structural proteins collagen and elastin, which reside within the extracellular matrix (ECM) of the arterial tissue. It has long been established that much of the mechanical non-linearity associated with arterial tissue is the result of collagen mechanics. Arterial collagen is arranged within the vascular wall as tortuous fibrils with a bulk fiber orientation of roughly helical configuration. When arterial tissue is deformed, these collagen fibers become straightened in the direction of applied load. At some critical deformation, termed the transition stretch (λTrans), collagen fibers begin to carry load, thus significantly altering material stiffness. This in turn gives rise to the non-linear force-stretch (F-λ) response typical of these tissues, Figure 1. We have recently found that λTrans is significantly reduced in the hypoxia-induced pulmonary hypertensive (PH) rat model. We therefore propose that this model constitutes an ideal system to study the effect of collagen microstructure on the mechanics of arterial tissues in response to PH vascular remodeling. We hypothesize that quantitative characterization of collagen microstructure will predict pulmonary artery (PA) λTrans within this model system. By directly relating collagen microstructural changes to bulk tissue mechanics in response to PH-induced vascular remodeling we can better understand how changes in collagen structure impact pulmonary hemodynamic capacitance, a major component of cardiac load and contributing factor to right heart failure.

Recent studies indicate that vascular stiffening and associated remodeling of the proximal pulmonary arteries, due to pulmonary hypertension, may play a critical role in the progression of the disease and ultimate cardiac failure [1]. While progress has been made in the understanding of active and passive arterial mechanics of whole arteries, comparatively little experimental work has been done on the role of the major extracellular structural proteins, collagen and elastin, in determining baseline arterial mechanics and modulating behavior during vascular remodeling [2, 3]. Here, we examine the methods to determine the specific role of elastin in arterial mechanics as it relates to pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is characterized as a chronic elevation in mean pulmonary artery pressure (MPAP) resulting from increased hydrodynamic resistance and decreased hydraulic capacitance of the pulmonary circulatory system. These hemodynamic changes cause the heart to operate outside optimum pump efficiency. The heart compensates for the efficiency loss through ventricular hypertrophy which, if left untreated, will continue until cardiac failure results.