Effects of Sex on the Elastogenesis of Vascular Elastic Fibers

PROJECT SUMMARY – Effects of Sex on the Elastogenesis of Vascular Elastic Fibers Elastic fibers and laminae are responsible for compliance and elastic recoil in many tissues, including arteries. The production of mature elastic structures occurs during late fetal and early neonatal periods and is thought to

cease in adulthood. Though these structures are mechanically and chemically stable, long human lifespans subject elastin to cyclic mechanical stress and proteolytic destruction that increase arterial stiffness and lead to a myriad of cardiovascular events, including hypertension, cardiomyopathy, kidney disease, and peripheral

arterial disease, that are often delayed in women compared to men. Elastin regeneration could help avoid arterial stiffening but has not been described in adult human tissues. Our recent analysis demonstrates that elastic fibers in the external elastic lamina (EEL) of human femoropopliteal arteries (FPAs) often contain long breaks filled by

thinner continuous fibers that have a different pitch than the rest of the EEL. These breaks are present in both young healthy arteries with no vascular pathology or inflammation, and in old diseased arteries. Elastic fibers filling these breaks are autofluorescent, and stain positive for Verhoeff-Van Gieson and periodic acid-Schiff

stains, indicating the presence of an elastin core and a higher proportion of microfibrillar structure typical of a newly synthesized fiber. In combination with animal model findings suggesting that pregnancy incites a burst in elastic fiber synthesis in the vaginal tissue, these data allow hypothesizing that the production of continuous

vascular elastic fibers occurs in maturity and that the female sex has a positive effect on this process, which may partially explain the sex-related vascular health disparities. To test this hypothesis, we will first determine whether the elastic fibers filling EEL breaks in healthy arteries are newly synthesized or are

undergoing degradation using human FPAs from tissue donors and performing biaxial mechanical characterization, constitutive modeling, multiphoton microscopy, histological/immunohistochemical analyses, and mass spectrometry to compare the biomechanics, microstructure, and molecular characteristics of segments

with and without the breaks. Second, we will determine if women have a greater proportion of filled EEL breaks than men using an existing histological biobank from >1,000 human FPAs available in the Tissue Analysis Core (TAC). Statistical modeling and machine learning will help determine ethnic and risk factors contributing to filled

EEL breaks in women and men of different ages. This project will leverage the unique resource of human arteries and TAC’s expertise to challenge the existing paradigm that the production of continuous elastic fibers does not occur in maturity. It will determine if the elastin modification process is different in women than in men, which

could help explain the frequently delayed onset of vascular disorders in women. Proving or disproving this hypothesis will open numerous research avenues to investigate either the mechanisms of functional elastogenesis or elastic fiber degradation without inflammation, which can both be harnessed for the

development of novel therapies and drug-coated materials and devices to aid with vascular regeneration.