The underlying role of pericyte-related cerebral lymphatic microcirculation dysfunction in cerebral small vessel disease

Cerebral small vessel disease (cSVD), a leading cause of stroke and cognitive impairment, is characterized by varied neuropathological features and neuroimaging findings, including enlarged perivascular spaces (EPVS), white matter hyperintensities (WMH), cerebral microbleeds (CMB), and cerebral subcortical ischemic lesions. The pathogenesis of cSVD has mainly been attributed to disruptions in blood circulation, such as arteriosclerosis, blood-brain barrier leakage, and reduced cerebral blood flow. However, many questions about the complex clinical and neuroimaging manifestations of cSVD remain. Growing evidence underscores the critical role of cerebral lymphatic system dysfunction in cSVD pathogenesis. The glymphatic system (GS) and intramural peri-arterial drainage (IPAD)-despite lacking the structure of lymphatic vessels in brain parenchyma, play critical roles in draining and clearing waste, akin to the cerebral lymphatic system. Pericytes, recognized as a key regulator of cerebral lymphatic microvascular function, have emerged as critical components of this system through their roles in with aquaporin-4 (AQP4) polarity and basement membrane remodeling. This review first provides a brief overview of cSVD, followed by a discussion of the role of pericytes in GS and IPAD, introducing the novel concept of pericyte-related cerebral lymphatic microcirculation. Finally, the involvement of pericyte-related cerebral lymphatic microcirculation in the pathophysiology of various subtypes of cSVD is explored. Elucidation of the mechanisms underlying cerebral lymphatic microcirculation disorder in cSVD expected to facilitate the development of therapeutic and preventive strategies for cSVD.