Exercise Rescues Blood-Brain Barrier Structural Impairment and Enhances Mitochondrial Biogenesis in a Hypertensive Mouse Model

Purpose. Blood-brain barrier (BBB) dysfunction is implicated in various neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. Over the past decades, numerous studies have suggested that exercise can mitigate neurodegenerative processes by improving mitochondrial function. Recently, we demonstrated that exercise could reverse hippocampus-associated memory deficits and reduce BBB leakage in a modified two-kidney, one-clip (2K1C) hypertensive animal model. Based on these findings, we hypothesize that exercise restores BBB integrity in hypertensive animal models. Methods. Hypertension was induced in C57BL/6 mice via 2K1C surgery. Following three weeks of hypertension induction, mice underwent moderate-intensity treadmill exercise for five weeks. Subsequently, brain tissues were collected for immunofluorescence staining and immunoblotting analyses to assess changes in BBB structure and mitochondria-related protein expression. Results. Exercise restored hypertension-induced reductions in blood vessel density within the hippocampus. Additionally, it repaired BBB structural impairments, as evidenced by increased levels of Claudin-5 co-localization with blood vessels, enhanced perivascular astrocyte levels, and improved perivascular AQP-4 protein expression. An immunoblotting analysis revealed that exercise upregulated the PGC-1α/Nrf1/UCP-2 pathway in the 2K1C hypertensive model. However, exercise did not significantly affect Drp-1 expression. Conclusions. Exercise alleviates BBB leakage by restoring structural integrity to the BBB. These improvements may be mediated through the enhancement of mitochondrial biogenesis.