G Protein-Coupled Receptors in Cerebrovascular Diseases: Signaling Mechanisms and Therapeutic Opportunities.

G protein-coupled receptors (GPCRs) are key regulators of cerebrovascular function, integrating vascular, inflammatory, and neuronal signaling within the neurovascular unit (NVU). Increasing evidence suggests that GPCR actions are highly dependent on cell type, signaling pathway, and disease stage, leading to distinct, and sometimes opposing, effects during acute ischemic injury and post-stroke recovery. In this review, we reorganize GPCR signaling mechanisms using a disease-stage-oriented and NVU-centered framework. We synthesize how GPCR-mediated intercellular communication among neurons, glial cells, and vascular elements dynamically regulates cerebral blood flow, neuroinflammation, blood-brain barrier (BBB) integrity, and neuronal circuit remodeling. Particular emphasis is placed on phase-dependent GPCR signaling, highlighting receptors whose functions shift across acute injury, secondary damage, and recovery phases. We further critically evaluated the translational implications of GPCR-targeted therapies, discussing why promising preclinical neuroprotection has frequently failed to translate into clinical benefit. By integrating molecular mechanisms with temporal dynamics and translational constraints, this review provides a framework for the rational development of cell-type and stage-specific GPCR-based therapeutic strategies in cerebrovascular disease.