Single-cell transcriptomic analyses reveal angiogenic vascular responses to chronic cerebral hypoperfusion.

Elucidating the mechanisms underlying vascular injury and repair may guide development of therapies against vascular cognitive impairment and dementia (VD). We employed single-cell RNA sequencing to map cell populations and explore vascular responses in mouse brains collected 42 days after asymmetric common carotid artery stenosis (ACAS)-induced chronic cerebral hypoperfusion. A unique tip cell type was identified among endothelial cell (EC) clusters and validated by immunostaining. Gene Ontology analyses suggested tip cell enrichment in angiogenesis and the involvement of Apln/Aplnr signaling. Immunoblotting confirmed an increase in apelin (Apln) protein after ACAS. In EC cultures, [Pyr1]-Apelin-13 (Apln13), a selective endogenous apelin receptor agonist, enhanced EC proliferation, migration, and tube formation. Treatment with Apln13 also improved angiogenesis, white matter integrity, and cognitive functions in ACAS mice. Cell-cell interaction analyses highlighted astrocyte-tip cell crosstalk via Vegfa-Vegfr interactions.