Extracellular matrix (ECM) remodeling has been proposed as one mechanism by which proximal pulmonary arteries (PA) stiffen during pulmonary arterial hypertension (PAH). Although some attention has been paid to the role of collagen and metallomatrix proteins, less is known regarding how changes in the structure-function relationship of elastin affects pulmonary vascular stiffness (PVS) in the setting of PAH.

We have used biomechanical stress-strain testing to determine the structure-function relationships of fresh arterial tissue and digested arterial elastin from the PA branches of normotensive (N=3) and hypoxia-induced PAH (N=6) neonatal calves. Our results show that PAH causes in an average 46% and 84% increase in elastic modulus (E) and an 81% and 100% increase in PVS of fresh and elastin tissues respectively. Analysis of our stress-strain data further suggests that the increased pressure loading of PAH causes an overall increase in peak arterial strain but has no effect on the strain at which collagen recruitment occurs. Therefore, while diastolic strain and baseline E are determined by elastin mechanics, the strain at systole appears increasingly dependent on collagen as a result of PAH.

We conclude that mechanobiological adaptations of the continuum and geometric properties of elastin, in response to PAH, significantly elevate proximal artery PVS, and that this increased stiffness acts to maintain the hypertensive physiologic strain range within the more elastin dependent region of the stress-strain curve. These results indicate that therapies which reduce ECM stiffness may be useful in the treatment of PAH.

Funded By: NIH P50HL84923, NIH T32HL072738, NIH K24HL081506