Exercise preconditioning upregulates cerebral integrins and enhances cerebrovascular integrity in ischemic rats

We hypothesized that exercise preconditioning strengthens brain microvascular integrity against ischemia/reperfusion injury through the tumor necrosis factor (TNF)-integrin signaling pathway. Adult male Sprague Dawley rats (n = 24) were studied in: (1) exercise (the animals run on a treadmill 30 min each day) for 3 weeks, (2) non-exercise. Six animals from each group (n = 12) were subjected to stroke, the remaining animals served as controls (n = 6 x 2). Brain infarction and edema were determined by Nissl staining. Cerebral integrin expression was detected by immunochemistry and stereological methods. In addition, we used flow cytometry to address the causal role of TNF-alpha in inducing the expression of integrins in the human umbilical vein endothelial cells under TNF-alpha or vascular endothelial growth factor (VEGF) pretreatment. Exercise reduces brain infarction and brain edema in stroke. Expressions of integrin subunit alpha(1), alpha(6), beta(1), and beta(4) were increased after exercise. Exercise preconditioning reversed stroke-reduced integrin expression. An in vitro study revealed a causal link between the gradual upregulation of TNF-alpha (rather than VEGF) and cellular expression of integrins. These results demonstrated an increase in cerebral expression of integrins and a decrease in brain injury from stroke after exercise preconditioning. The study suggests that upregulation of integrins during exercise enhances neurovascular integrity after stroke. The changes in integrins might be altered by TNF-alpha.