Large Artery Atherosclerosis Induced Endothelial Senescence Increases Cerebral Microhemorrhage Vulnerability in Ldlr-KO Mice

Objective: Cerebral microhemorrhages (CMHs) are a characteristic feature of cerebral small vessel disease (CSVD). However, the mechanisms linking large artery atherosclerosis (LAA) to CMH vulnerability remain poorly understood. Here, we aimed to determine whether systemic atherosclerosis accelerates microvascular endothelial cell (EC) senescence in the brain causally increases the susceptibility to CMHs. Hypothesis: We hypothesized that LAA promotes senescence of cerebral microvascular ECs, generating a senescence-associated secretory phenotype (SASP) that weakens vessel integrity and markedly increases CMH formation. We further hypothesized that senolytic treatment with ABT263 would reduce senescent cell burden and protect against CMHs. Methods: Ldlr-knockout (Ldlr-KO) mice were fed a Western diet for 4 months to induce large artery atherosclerosis (LAA). Cerebral microhemorrhages (CMHs) were experimentally triggered using the induced hypertension model generated by chronic angiotensin II (Ang II) infusion combined with L-NAME administration. CMH number and volume were quantified via whole-brain serial sections stained with hematoxylin and diaminobenzidine (DAB) using automated slide scanning, and supervised machine-learning–based CMH detection. To evaluate the functional consequences of CMHs, gait performance was assessed. To assess neurological decline following hypertension-induced vascular stress, was measured using a standardized neurological deficit scoring. A subset of mice received the senolytic drug ABT263 to reduce senescent cell burden. Results: Ldlr-KO mice exhibited increased endothelial senescence compared to non-transgenic littermates. Following Ang II + L-NAME hypertension, Ldlr-KO mice showed a markedly higher CMH burden compared with wild-type and vehicle controls. CMHs produced functional impairments, including reduced stride symmetry and lower gait regularity. Neurological scoring demonstrated accelerated decline, and Kaplan–Meier analysis revealed increased neurological deficit in Ldlr-KO mice. Senolytic treatment with ABT263 decreased EC senescence, which eventually reduced CMH formation and ameliorated both gait deficits and neurological survival outcomes. Conclusions: Atherosclerosis-induced endothelial senescence creates a vulnerable cerebral microvascular state that markedly increases susceptibility to CMHs under hypertensive stress. Senescent cells are a causal driver of this fragility, and senolytic therapy significantly reduces CMH burden and associated neurological dysfunction. These findings identify endothelial senescence as a mechanistic link between large artery atherosclerosis and CSVD-related microbleeds and highlight senolytics as a potential therapeutic strategy. Funding source: Funding for this project was provided by NIH grant R01AG055395. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.