Chronic hindlimb ischemia exacerbates ischemic stroke by disrupting cerebral hemodynamics and glycerophospholipid metabolism in mice

While clinical data firmly establish that Peripheral artery disease is linked to a higher incidence and severity of ischemic stroke, the underlying hemodynamics and metabolic mechanisms remain poorly defined. This study aimed to elucidate how chronic limb ischemia remotely exacerbates ischemic stroke outcomes through these mechanisms. Computational fluid dynamics combined with high-resolution MRI was used to quantify cerebral hemodynamics, including wall shear stress (WSS), blood flow velocity, and wall pressure. Integrative omics was applied to analyze molecular changes. Focal cerebral ischemia was induced during chronic hindlimb ischemia to assess stroke outcomes. Our results showed that both WSS and blood flow velocity were significantly decreased in the model group compared with the sham group, particularly in the middle cerebral artery. Chronic hindlimb ischemia exacerbated brain edema, increased infarct volume by 1.5-fold, and worsened neurological deficits. Integrated omics analysis revealed disturbances in glycerophospholipid metabolism and identified phosphate cytidylyltransferase 2 (PCYT2) as a key upregulated protein. Crucially, in vivo functional validation demonstrated that silencing PCYT2 conferred significant neuroprotection, reducing infarct volume and improving neurological outcomes. These findings enhance our understanding of the pathogenesis mechanisms by which chronic limb ischemia aggravates ischemic stroke and provide new insights into its prevention and treatment.