Unwinding the Neurovascular Unit: The Vascular Extracellular Matrix and Mechanochemical Collagen Functionalization in...

Vascular dementia (VaD) represents a spectrum of neurodegenerative disorders driven by chronic or acute cerebral hypoperfusion, converging on the structural collapse of the neurovascular unit (NVU). While vascular mechanics and neuroinflammation have been extensively characterized, the extracellular matrix (ECM) remains an under-appreciated driver of this pathology. Far from being a passive scaffold, the ECM serves as a dynamic regulator of brain homeostasis, governing the integrity of the blood-brain barrier (BBB), supporting synaptic plasticity via Perineuronal Nets (PNNs), and facilitating the glymphatic clearance of metabolic waste. This review and perspective examines the pivotal role of the ECM within the "tripartite" NVU, the interface connecting vascular cells, CNS glia, and perivascular nerves. We discuss how the dysregulated activity of matrix metalloproteinases (MMPs) and the alteration of basement membrane components compromise the architectural defenses of the NVU. We describe how these structural failures can transform vascular insults into progressive neurodegenerative decline by unmasking inflammatory binding sites and disrupting cell-matrix signaling. Specifically, we highlight (1) the physiological architecture of the NVU and its dependence on specific collagen organization, (2) the mechanistic pathways of ECM disruption in VaD pathogenesis, including the feedback loop between ischemia and proteolysis, (3) the emerging therapeutic potential of targeting matrix components to restore neurovascular stability, and (4) a novel mechanochemical hypothesis framing pathological collagen functionalization as an epidemiological bimodal switch. Uncovering the interplay between structural remodeling and vascular function offers novel targets to halt the progression of dementia.