Sexually Dimorphic Transdifferentiation of Endothelial Cells in Atherosclerosis

In this study, we investigated sex-specific endothelial cell (EC) states and cell fate trajectories in atherosclerosis. Both male and female <i>Apoe</i>^{<em>−/−</em>}<i>/Cdh5-CreER</i>^<em>T2</em><i>/Rosa26-mTmG</i> mice were generated for EC-specific lineage-tracing and were fed a high-fat diet (HFD) to establish hypercholesterolemia and atherosclerosis.

Here we show that single-nucleus RNA sequencing (snRNA-seq) of plaque-bearing aortae identified nine sex-biased EC subpopulations, including capillary, lymphatic, <i>Sox17</i>, <i>Myh11</i>, <i>Mki67</i>, and <i>Ly6a</i> ECs enriched in females, and <i>Col8a1</i> and <i>Fmo2</i> ECs enriched in males. GeneTrajectory and lineage tracing indicated that approximately one quarter of GFP⁺ EC-lineage cells acquired adipocyte-like, SMC-like, or fibroblast-like states, with female-biased EC-to-SMC-like and male-biased EC-to-adipocyte-like transitions.Regulatory network analysis using <i>pySCENIC</i> implicated <i>Klf2</i> and <i>Creb5</i> in EC fate decisions in the context of atherosclerosis.