Simvastatin Ameliorates Lipid Metabolism-Mediated Endothelial Inflammation and Tight Junction Impairment in Chronic...

Chronic cerebral hypoperfusion (CCH) is a key pathological hallmark observable in multiple subtypes of cerebral small vessel disease (CSVD). This condition causes both structural and functional changes within the brain's vascular system, and is particularly damaging to brain microvascular endothelial cells (BMECs). The exact molecular mechanisms underlying BMEC impairment in CCH remain insufficiently defined despite their clinical importance. Emerging evidence indicates that disturbances in intracellular lipid metabolism might contribute substantially to promoting endothelial inflammation and functional deficits. This study aims to investigate whether aberrant lipid metabolism contributes to endothelial inflammation and tight junction (TJ) dysfunction in BMECs under the condition of CCH, and to assess the therapeutic potential of intervention with simvastatin. A rat model of chronic CSVD was created via permanent bilateral ligation of the common carotid arteries (2VO) in animal subjects. Samples of cortical microvasculature were collected at predefined intervals for transcriptome profiling. Assessments of lipid metabolism, inflammation-related factors, and TJ protein levels were conducted in both in vivo and after induction of hypoxia and administration of simvastatin. At 14d post-2VO, mRNA expression of TJ proteins including occludin (Ocln), claudin-5 (Cldn5), and zonula occludens-1 (Zo-1) was significantly downregulated in BMECs compared to sham controls. Simultaneously, there was a notable buildup of lipid droplets, rise in cholesterol levels, and upregulation of pro-inflammatory indicators including VCAM1, TNF-α, and ICAM1. Simvastatin administration effectively reduced lipid buildup, suppressed inflammation, and restored TJ integrity. Dysregulated lipid metabolism and heightened inflammatory responses contribute to TJ disruption in BMECs with CCH. Simvastatin therapy mitigates lipid accumulation, dampens inflammation, and improves TJ function in BMECs with CCH.