The HCG11/QKI5 Axis Regulates Endothelial Angiogenic Adaptation During Chronic Cerebral Hypoperfusion

Chronic cerebral hypoperfusion drives the progression of intracranial atherosclerotic stenosis (ICAS) and increases ischemic risk. Endothelial angiogenic adaptation initially preserves cerebral perfusion but deteriorates with disease progression. We investigated whether the HCG11/QKI5 axis represents a regulatory node with therapeutic potential in cerebral hypoperfusion.

Circulating hypoxia- and angiogenesis-related biomarkers were compared between asymptomatic and symptomatic ICAS patients to reflect different progression stages. Endothelial function was assessed in oxygen-glucose deprivation models following HCG11 overexpression or QKI5 knockdown. A rat model of chronic cerebral hypoperfusion was used to evaluate temporal changes in vivo.

Pro-angiogenic factors were elevated in asymptomatic ICAS but reduced in symptomatic patients, indicating progressive impairment of vascular compensation. HCG11 overexpression enhanced endothelial proliferation and tube formation, whereas QKI5 silencing attenuated these responses. These effects were associated with modulation of HIF-1α/VEGF signaling. In vivo, early hypoperfusion activated QKI5 and angiogenic pathways, followed by a gradual decline during sustained hypoperfusion.

Progressive attenuation of the HCG11/QKI5-mediated angiogenic program may underlie endothelial adaptive failure in cerebral hypoperfusion. Targeting this RNA-regulatory axis may represent a potential therapeutic strategy to preserve vascular compensation and mitigate disease progression in ICAS.