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Unraveling the role of sex in endothelial cell dysfunction – Evidence from lineage tracing mice and cultured cells

ABSTRACT: Background: Biological-sex differences play a vital role in cardiovascular diseases, including atherosclerosis. The endothelium is a critical contributor to cardiovascular pathologies since endothelial cells (EC) regulate vascular tone, redox balance, and inflammatory reactions. Although EC activation and dysfunction play an essential role in the early and late stages of atherosclerosis development, little is known about sex-dependent differences in EC. Methods: We used aortic EC that was isolated from 13-week-old female and male mice as well as EC-lineage tracing (Cdh5-CreERT2 Rosa-YFP) atherosclerotic Apoe‒/‒ mice to investigate the biological sexual dimorphism of the EC functions in vitro and in vivo. RNA sequencing (RNAseq) analyses were performed on male and female mouse aortic EC and human lung EC. Results: In vitro, female mouse aortic EC (F_MAEC) showed more apoptosis and higher cellular ROS levels, lower mitochondrial membrane potential (ΔΨm), and lower levels of mitochondrial transcription factor A (TFAM) than male aortic EC (M_MAEC). Additionally, F_MAEC had decreased angiogenic potential (tube formation, cell viability, and proliferation) compared to M_MAEC. In vivo, female mice had significantly higher lipid accumulation within the aortas, less efficient outward vessel remodeling, and lower endothelial-mediated vasorelaxation than males. Using the EC-lineage tracing approach, we found that female lesions had significantly lower rates of intraplaque neovascularization and Endothelial-to-Mesenchymal (EndoMT) transition within advanced atherosclerotic lesions but higher incidents of missing EC lumen coverage and higher levels of oxidative products and apoptosis. RNAseq analyses revealed that both mouse and human female EC had higher expression of genes associated with inflammation and apoptosis and lower expression of genes related to angiogenesis and oxidative phosphorylation than male EC. Conclusions: Our study delineates critical sex-specific differences in EC relevant to pro-inflammatory, pro-oxidant, and angiogenic characteristics, which are entirely consistent with a vulnerable phenotype in females. Our results provide a biologic basis for sex-specific pro-atherosclerotic mechanisms.

ORGANISM(S): Mus musculus

PROVIDER: GSE247364 | GEO | 2023/11/30

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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Unraveling the role of sex in endothelial cell dysfunction – Evidence from lineage tracing mice and cultured cells

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