Blood-Brain Barrier Damage as the Starting Point of Leukoaraiosis Caused by Cerebral Chronic Hypoperfusion and Its Involved Mechanisms: Effect of Agrin and Aquaporin-4

Abstract

White matter lesion (WML) is popular in the patients aged over 65. Brain edema and blood-brain barrier (BBB) dysfunction due to cerebral chronic hypoperfusion (CCH) contributed to WML. Preserving astrocyte polarity is vital for BBB integrity. In our experiment, CCH model is established by bilateral carotid arteries occlusion (2VO). Leukoaraiosis was verified by fiber density stain, and brain edema was evaluated using brain water content measuring. The expressions of agrin and aquaporin-4 (AQP4) were evaluated, as well as the integrity of BBB. Astrocyte polarity was assessed by visualizing the distribution of AQP4 on astrocyte end-feet membranes. The results showed that expression of AQP4 firstly increased and then decreased, as agrin expression decreased gradually. At 3 days after 2VO, AQP4 and agrin displayed the most opposite expression with the former increasing and the latter decreasing; at the same time, brain edema reached high point as well as BBB permeability, and astrocyte polarity was degeneration. In the later phase, brain edema and BBB permeability were getting recovered, but WML was getting more evident. In accordance with that, agrin and AQP4 expression decreased significantly with astrocyte polarity reducing. We speculated that agrin and AQP4 played key roles in development of WML by mediating BBB damage in CCH, and BBB dysfunction due to reduced astrocyte polarity is the starting point of WMH.