Disease-specific dominant signalling pathways and signatures in cerebrovascular diseases

Abstract Cerebrovascular diseases (CVDs) comprise a heterogeneous group of brain diseases, including stroke, cerebral small vessel disease (CSVD), cerebral amyloid angiopathy (CAA), and vascular dementia (VaD), driven by distinct yet overlapping vascular and cellular mechanisms. Advances in molecular medicine and omics technologies have identified disease-specific dominant signalling pathways and molecular signatures that govern disease initiation, progression, and clinical outcomes, offering a basis for precision therapeutics. In acute CVDs, ischaemic stroke is characterised by abrupt hypoperfusion activating hypoxia-inducible factor ( HIF-1α ), glutamate–NMDA receptor excitotoxicity, stress-activated MAPK cascades, NF- κB – and inflammasome-mediated sterile inflammation, and PI3K/Akt–mTOR survival signalling, forming a dynamic injury–repair continuum. Haemorrhagic stroke is dominated by blood-derived signalling, including thrombin–protease-activated receptor activation, haemoglobin/haem–TLR4 signalling, oxidative stress, ferroptosis, matrix metalloproteinase–mediated extracellular matrix degradation, and complement activation, leading to rapid blood–brain barrier disruption and amplified innate immune responses. Chronic CVDs exhibit sustained neurovascular dysfunction. CSVD is defined by endothelial nitric oxide dysregulation, TGF-β /SMAD overactivation, NOTCH3 signalling abnormalities, and pericyte–endothelial uncoupling, supporting a vascular-first paradigm. CAA involves amyloid-β deposition impairing vascular clearance and promoting chronic inflammation, while VaD arises from prolonged hypoperfusion, endothelial stress, oxidative injury, and low-grade inflammation, culminating in progressive cognitive decline. Overall, delineating disease-specific signalling networks and molecular signatures across acute and chronic CVDs enables biomarker discovery, phase-specific therapeutic targeting, and neurovascular unit–focused interventions, providing a unified framework for advancing precision strategies to improve clinical outcomes.