Microvessel hypoperfusion following ischemic stress resulted in a decreased shear stress of brain microvascular endothelial cells (BMECs) and contributed to abnormal expression of PECAM-1 after global cerebral ischemia/reperfusion (I/R) injury. Here, we identified novel pathophysiologic and rehabilitative procedures specific to shear stress in microvascular endothelial cells in response to global cerebral I/R injury. We found that the decrease in cerebral blood flow of gerbils after global cerebral I/R injury reduces shear stress, and the abnormal change in shear stress leads to microvascular endothelial cell and neuron damage. Nevertheless, suitable high levels of shear stress contribute to rescuing the dysfunction and malformation of BMECs via regulating the PECAM-1-eNOS-NO pathway to enhance nitric oxide release, decrease the expression of caspase-3 to reduce apoptosis, and improve the shear-adaptability of endothelial cells, thereby playing a protective role in the gerbil brain.