RESUMO
Aortic valve stenosis (AVS) is a progressive disease wherein males develop valve calcification relative to females that develop valve fibrosis. Valvular interstitial cells (VICs) aberrantly activate to myofibroblasts during AVS, driving the fibrotic valve phenotype in females. Myofibroblasts further differentiate into osteoblast-like cells and secrete calcium nanoparticles, driving valve calcification in males. We hypothesized the lysine demethylase UTY (ubiquitously transcribed tetratricopeptide repeat containing, Y-linked) decreases methylation uniquely in response to nanoparticle cues in the valve extracellular matrix to promote an osteoblast-like phenotype. Here, we describe a bioinspired hydrogel cell culture platform to interrogate how nanoscale cues modulate sex-specific methylation states in VICs activating to myofibroblasts and osteoblast-like cells. We found UTY (ubiquitously transcribed tetratricopeptide repeat containing, Y-linked) modulates VIC phenotypes in response to nanoscale cues uniquely in males. Overall, we reveal a novel role of UTY in the regulation of calcification processes in males during AVS progression.
RESUMO
Biological sex differences are observed at multiple different length scales and across organ systems. Gaps in knowledge remain regarding our understanding of how molecular, cellular, and environmental factors contribute to physiological sex differences. Here, we provide our perspective on how chemical and molecular tools can be leveraged to explore sex differences in biology at the molecular, intracellular, extracellular, tissue, and organ length scales. We provide examples where chemical and molecular tools were used to explore sex differences in the cardiovascular, nervous, immune, and reproductive systems. We also provide a future outlook where chemical and molecular tools can be applied to continue investigating sex differences in biology, with the ultimate goal of addressing inequities in biomedical research and approaches to clinical treatments.