Epigenetic Reactivation of CNS Endothelial Developmental Programs Triggers Adult Brain Angiogenesis, Promotes Post-Stroke Revascularization and Neuronal Regeneration

Therapeutic angiogenesis is essential for regenerating brain tissue damaged by stroke, yet it remains an unmet clinical challenge. During brain development, pro-angiogenic genes drive the formation of vascular networks, with their expression tightly regulated in later stages. We found that in adult CNS endothelial cells (ECs), angiogenesis-related genes are epigenetically silenced through histone deacetylase 2 (HDAC2) and the polycomb repressive complex 2 (PRC2). Conditional deletion of Hdac2 in ECs reactivated pro-angiogenic signaling, including Wnt/β-catenin target genes, leading to functional neovascularization with preserved blood-brain barrier (BBB) integrity in the adult brain. In contrast, Ezh2 (PRC2 subunit) deletion reduced vessel density and compromised BBB function. Deletion of Hdac2 and Ezh2 immediately after transient ischemic stroke conferred vascular protection by modulating stroke-induced transcriptional programs in CNS ECs. In contrast, delayed deletion, initiated seven days post-stroke, after significant neuronal loss in the infarct region, induced robust revascularization and promoted post-stroke neurogenesis, with differentiation into both excitatory and inhibitory neurons. These findings highlight CNS EC HDAC2 as a promising therapeutic target for inducing adult brain angiogenesis, facilitating revascularization, and supporting neuronal regeneration following stroke.