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bioRxiv · 10.64898/2026.09.27.754749

Low-Density Lipoprotein Cholesterol and Cerebral Pericyte Dysfunction in Acute Ischemic Stroke: Clinical and Experimental Evidence

Wang, F.·Quan, W.·Wu, G.·Yang, J.·Wang, X.·Cao, Q.·Hao, W.·Wang, E.·Furihata, T.·Xu, W.·Li, D.·Ke, S.·Liu, Y.
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Abstract

Background: Low-density lipoprotein cholesterol (LDL-C) is an established risk factor for atherosclerotic cerebrovascular disease, but its effects on the cerebral microcirculation are poorly defined. We investigated whether LDL-C is associated with pericyte dysfunction in acute ischemic stroke (AIS) and explored underlying mechanisms. Methods: Serum soluble platelet-derived growth factor receptor-{beta} (sPDGFR{beta}) was measured in two independent AIS cohorts (n=97 and n=86). Cerebral pericyte transcriptional responses to LDL-C were analyzed by single-cell RNA sequencing in Apoe-knockout mice fed control or high-fat diet (n=4 [male/female: 2/2]/group), and cultured human brain pericytes were exposed to purified human LDL cholesterol with or without N-acetyl-L-cysteine. Results: Higher serum sPDGFR{beta} was associated with greater neurological deficit and circulating neurofilament light chain. LDL-C positively correlated with sPDGFR{beta} in both clinical cohorts. High-fat diet induced coordinated suppression of type-I interferon pathways, and a positive shift in reactive oxygen species-related transcriptional programs in mouse pericytes; exploratory sex-by-diet analyses suggested larger transcriptional responses in females. In cultured human pericytes, LDL-C induced oxidative-stress, lipid-handling, and ferroptosis-associated transcriptional programs while suppressing type-I interferon signaling. Cross-species enrichment analysis showed that LDL-C-induced and -repressed signatures in cultured pericytes aligned with the sex-by-diet interaction in Apoe-knockout mice. LDL-C also reduced cell-surface PDGFR{beta} and increased sPDGFR{beta} release in cultured pericytes, which were significantly attenuated by N-acetyl-L-cysteine, whereas LDH activity increased numerically but not significantly. Conclusions: Clinical and experimental findings support an LDL-pericyte axis linking atherogenic lipid stress to cerebral microvascular dysfunction, with possible sex-dependent modulation of oxidative stress and type-I interferon signaling as potential mechanisms.

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Wang, F., Quan, W., Wu, G., Yang, J., Wang, X., Cao, Q., Hao, W., Wang, E., Furihata, T., Xu, W., Li, D., Ke, S., Liu, Y.. 2026-10-02. Low-Density Lipoprotein Cholesterol and Cerebral Pericyte Dysfunction in Acute Ischemic Stroke: Clinical and Experimental Evidence. https://doi.org/10.64898/2026.09.27.754749

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