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

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-β (sPDGFRβ) 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 sPDGFRβ was associated with greater neurological deficit and circulating neurofilament light chain. LDL-C positively correlated with sPDGFRβ 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 PDGFRβ and increased sPDGFRβ 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.

Clinical Perspective

What Is New?

• In two independent AIS cohorts, circulating sPDGFRβ was independently associated with LDL cholesterol, linking a conventional atherosclerotic risk factor to a marker of cerebral pericyte dysfunction.

• Experimental models showed that atherogenic lipid exposure induces oxidative/lipid-stress programs and suppresses type I interferon signaling in pericytes, with a more pronounced high-fat-diet transcriptional response in females.

What Are the Clinical Implications?

• LDL lowering may protect the cerebral microcirculation in addition to preventing large-artery atherosclerosis, but prospective studies and stroke models are needed before pericyte-directed or sex-specific treatment implications can be established.