Hydrogel matrices to study the role of inflammation and biological sex on aortic valve fibrocalcification

ABSTRACT Thirteen percent of adults over 75 suffer from aortic valve stenosis (AVS), a progressive disease that leads to aberrant collagen deposition, leaflet stiffening, and eventual valve calcification at late stages. AVS is also sexually dimorphic with men having a two-fold higher risk for developing direct calcification, whereas women with equal disease severity tend to have more valvular fibrosis prior to calcification. The molecular mechanisms underlying sexual dimorphism in AVS progression remain poorly understood, but growing evidence suggests AVS is an inflammation-dependent disease. Sex is known to influence the magnitude of the immune response and function, so we propose to investigate the role of inflammation in sex-specific valve disease progression. We hypothesize that three major variables contribute to differences in valve calcification in male and female patients: (1) heightened myofibroblast activation in female valve cells when exposed to inflammatory cues, (2) elevated expression of bone mineralization inhibitors, such as osteopontin, in female valve cells, and (3) sex- specific differences in epigenetic machinery. To test these hypotheses, we will develop sex-specific in vitro models of fibro-calcification that are comparable to diseased valve tissue. We will then investigate the sex- specific role that macrophage and valvular interstitial cell (VIC) crosstalk has on AVS (Aim 1) and determine the role of epigenetics in sex-specific regulation of calcification regulators (Aim 2). Ultimately, we aim to identify sex- specific therapies targeted to VIC populations to slow or halt AVS disease progression (Aim 3).