ACE2 at the neurovascular–glymphatic interface: integrating the ACE2/ang-(1–7)/mas axis with brain fluid homeostasis and waste clearance

Background and aim Brain fluid homeostasis relies on coordinated interactions among the glymphatic system, intramural peri-arterial drainage, meningeal lymphatics, cerebrospinal fluid circulation, and the neurovascular unit (NVU). Emerging evidence indicates that angiotensin-converting enzyme 2 (ACE2) regulates multiple components of this integrated clearance network. This review examines the mechanistic role of ACE2 in cerebral fluid homeostasis and its relevance to neurological disease.Methods A narrative review of experimental, translational, and clinical studies published between 2000 and 2026 was performed using PubMed, Scopus, Web of Science, and Google Scholar. Evidence linking ACE2 signaling with neurovascular integrity, glymphatic transport, blood–brain barrier function, astrocytes, pericytes, and neurological disorders was critically evaluated.Results ACE2/Ang-(1–7)/Mas signaling is associated with endothelial and neurovascular mechanisms relevant to cerebral fluid homeostasis, including regulation of vascular tone, oxidative stress, inflammatory signaling, and BBB integrity. These effects may create a cellular and vascular environment compatible with appropriate AQP4 organization and perivascular fluid transport. However, direct ACE2-dependent regulation of AQP4 polarization, glymphatic transport, IPAD, or whole-brain waste clearance has not been established.Conclusion ACE2/Ang-(1–7)/Mas signaling represents a plausible modulatory pathway linking neurovascular, inflammatory, and cellular mechanisms relevant to brain fluid homeostasis. Its proposed effects on AQP4 organization and cerebral clearance remain predominantly indirect and require direct experimental and human validation before ACE2 can be considered a therapeutic regulator of these pathways.