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Aortic valve stenosis serum IGFBP2 mediates female-specific Evogliptin resistance in valve myofibroblasts

ABSTRACT: Aortic valve stenosis (AVS) is a sexually dimorphic cardiovascular disease characterized by fibro-calcification of the aortic valve leaflet. Sex differences in AVS arise in part from sexually dimorphic serum composition that differentially regulates valvular interstitial cell (VIC) myofibroblast activation. However, how individual serum factors contribute to sex-specific drug responses remains unknown. Here, we integrate serum proteomic profiling with in vitro drug screening using hydrogel biomaterials to identify sex-specific regulators of antifibrotic drug efficacy. We found that serum Insulin-like Growth Factor Binding Protein 2 (IGFBP2) mediates Evogliptin resistance in female VICs cultured with female AVS serum through the activation of Rho/ROCK and focal adhesion kinase signaling. Our findings highlight IGFBP2 as a candidate biomarker for stratifying female AVS patients for Evogliptin treatment, underscoring the need to incorporate sex as a biological variable in determining AVS treatments.

ORGANISM(S): Sus scrofa

PROVIDER: GSE316678 | GEO | 2026/06/23

REPOSITORIES: GEO

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Project description:Aortic valve stenosis (AVS) is a sexually dimorphic disease, with women often presenting with sustained fibrosis and men with more extensive calcification. However, the intracellular molecular mechanisms that drive these clinically important sex differences remain under explored. Hydrogel scaffolds were designed to recapitulate key aspects of the valve tissue microenvironment and serve as a platform for culture of sex-specific valvular interstitial cells (VICs; precursors to pro-fibrotic myofibroblasts). The hydrogel culture system was used to interrogate intracellular pathways involved in sex-dependent VIC-to-myofibroblast activation and deactivation. RNA-seq was used to define pathways likely to be involved in driving sex-dependent activation. Interventions using small molecule inhibitors were performed to provide mechanistic insight into sex-specific cellular responses to microenvironmental cues, including matrix stiffness and exogenously delivered biochemical factors. In both healthy porcine and human aortic valves, female leaflets had higher baseline activation of the myofibroblast marker, α-smooth muscle actin (α-SMA), compared to male leaflets. When isolated and cultured, female VICs had higher levels of basal α-SMA stress fibers that further increased in response to the hydrogel matrix stiffness, both of which were higher than male VICs. A transcriptomic analysis of male and female porcine VICs revealed Rho-associated protein kinase (RhoA/ROCK) signaling as a potential driver of this sex-dependent myofibroblast activation. Further, we found that genes that escape X-chromosome inactivation, such as BMX and STS (encoding for Bmx non-receptor tyrosine kinase and steroid sulfatase, respectively) partially regulate the elevated female myofibroblast activation via RhoA/ROCK signaling. This finding was confirmed by treating male and female VICs with endothelin-1 and plasminogen activator inhibitor-1, factors that are secreted by endothelial cells and known to drive myofibroblast activation via RhoA/ROCK signaling. Together, in vivo and in vitro results confirm sex-dependencies in myofibroblast activation pathways, and transcriptome analyses and small molecule interventions implicate genes that escape X-chromosome inactivation in regulating sex differences in AVS progression. Our results underscore the importance of considering sex as a biological variable to understand the molecular mechanisms of AVS and help guide sex-based precision therapies.

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Aortic valve stenosis serum IGFBP2 mediates female-specific Evogliptin resistance in valve myofibroblasts

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