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

TL;DR

This paper reviews how G protein-coupled receptors regulate brain blood vessel function and how targeting them could lead to new treatments for cerebrovascular diseases.

Contribution

The paper introduces a novel framework for understanding GPCR signaling in cerebrovascular diseases based on disease stages and cell-specific roles.

Findings

GPCR signaling varies significantly depending on the disease stage and cell type involved.

Targeting GPCRs with stage-specific strategies may improve therapeutic outcomes in cerebrovascular diseases.

Preclinical success in GPCR-based therapies has not consistently translated to clinical benefits due to complex signaling dynamics.

Abstract

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.

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