Astrocyte-mediated angiogenesis in CNS diseases: mechanisms and therapeutic implications.

Abstract

Astrocytes are central, yet often underappreciated, regulators of angiogenesis in the central nervous system (CNS), exhibiting a profound context-dependent duality. They can foster restorative vascular repair after ischemic injury while simultaneously driving pathological vessel formation in tumors and other neurological disorders. This review synthesizes current knowledge on astrocyte-mediated angiogenesis across major CNS diseases, critically examining how disease-specific cues-such as hypoxia, tumor-derived factors, or Aβ plaques-are integrated to produce distinct vascular outcomes. We move beyond the binary A1/A2 paradigm to introduce a framework of "disease-associated astrocyte subsets" (e.g., ischemia-associated, glioma-associated, and Alzheimer's disease-associated astrocytes), as revealed by emerging single-cell studies. Key mechanisms are dissected, including the tightly regulated VEGF/Ang axis, HMGB1 signaling, the Sonic Hedgehog pathway, and the growing role of exosomal miRNA transfer. A central challenge highlighted is the temporal dichotomy of VEGF action, which transitions from acutely detrimental to beneficial during recovery. We explore therapeutic implications, from promoting reparative angiogenesis in ischemia to inhibiting pathological angiogenesis in glioblastoma. By identifying critical knowledge gaps, we propose future directions-such as astrocyte-specific gene editing and engineered exosomes-that aim to translate these insights into effective, context-specific CNS therapies.