Aortic valve stenosis is a sexually dimorphic disease, whereby women tend to present with more fibrosis and less calcification in the valve leaflets than men. The only treatment for aortic valve stenosis is valve replacement. A better understanding of the molecular mechanisms underlying these differences could help in the design of drug treatments, which are currently lacking. Aguado and colleagues now show cell-intrinsic sex-specific differences in the pathways that drive the conversion of valvular interstitial cells (VICs) to myofibroblasts, and that these are partially driven by genes that escape X-chromosome inactivation (XCI).
The authors analyzed healthy porcine and human valves and observed that female valves had denser collagen fibers and more α-smooth muscle actin (α-SMA) stress fibers at baseline than did male valves. To understand the basis of these differences, they cultured male and female VICs on hydrogel matrices with different stiffness, recapitulating in vitro the valve extracellular matrix. They validated that seeded female VICs were more readily converted into activated myofibroblasts than were male VICs, both on soft gels and on stiff gels and in the absence of increased cell proliferation. Transcriptomic comparison of male and female VICs, cultured under conditions promoting either the fibroblast or myofibroblast phenotype, showed that the male VICs–myofibroblasts were uniquely enriched for the RhoA–ROCK pathway. The authors showed that male VICs were more responsive than female VICs to an inhibitor of RhoA–ROCK, at all concentrations and on all substrates. Through the use of small-molecule inhibitors and silencing via small interfering RNAs, they showed that the RhoA–ROCK pathway hyperactivation in female VICs was at least partially linked to higher expression of XCI-escape genes such as BMX and STS. Inhibition of those genes increased the response of female VICs to RhoA–ROCK inhibitors and reduced the myofibroblast conversion after treatment with the RhoA–ROCK upstream signals ET-1 and PAI-1.
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