Sponsor: Amparo Villablanca, M.D. MED: Int Med Cardiology (davis) Type 2 diabetes (T2D) is a risk factor for cardiovascular disease and cerebrovascular disease, including vascular dementia. Both T2D and vascular dementia affect men and women disproportionately. This study aims to understand the molecular mechanisms underlying sex differences in T2D-associated vascular dementia, focusing on endothelial cells in the hippocampus, an important brain memory center. We utilized females and males of the db/db, a T2D murine model, compared with sex-/age-matched wildtypes, and performed single nuclei RNA sequencing (snRNAseq) to assess sex divergent and in common responses. Cognitive function was measured using the Morris water maze test. db/db male and female mice exhibited a more similar endothelial transcriptomic profile compared with WT mice. Compared to males, females showed a four-fold increase in T2D-induced differentially expressed genes, greater gene ontology networks and cellular pathways. The female-specific pathways were involved in endothelial dysfunction, blood-brain barrier disruption, and neurodegeneration, whereas the male- specific pathways were involved in neuroinflammation and oxidative stress. Moreover, focal adhesion is one of the pathways altered by T2D in both males and females. Further, female db/db mice exhibited earlier cognitive dysfunction than males. Thus, our work has implications for sex-specific molecular therapeutic targets for T2D-linked vascular dementia. Dose-Dependent Bronchiolar Injury Following Acute Inhalation Exposure of Chloropicrin in Mice

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