The interplay between neuroinflammation and endothelial dysfunction in cerebral small vessel disease

Cerebral small vessel disease (CSVD) is a leading cause of ischemic stroke and vascular cognitive impairment. Despite well-defined neuroimaging features and a substantial clinical burden, the underlying pathological mechanisms of CSVD remain poorly understood, and effective interventions are still lacking. Current human and experimental evidence suggest that endothelial dysfunction and neuroinflammation are closely coupled and may form a mutually reinforcing process in many CSVD-relevant settings. This review synthesizes available evidence into a working framework in which vascular risk factors promote endothelial phenotypic switching and blood-brain barrier (BBB) dysfunction, thereby facilitating neuroinflammatory activation. Pericytes, astrocytes, and microglia within the neurovascular unit can then amplify barrier injury and inflammatory signaling through context-dependent feedback interactions, including matrix metalloproteinase-mediated proteolysis. In turn, the chronic inflammatory milieu may sustain persistent endothelial dysfunction or alter endothelial responsiveness to subsequent inflammatory stimuli, potentially allowing pathological processes to continue even after the original triggers are attenuated. Based on this evidence-guided framework, we also evaluate therapeutic strategies directed at distinct nodes of the endothelial dysfunction-neuroinflammation network.