The molecular mechanism of RIC-mediated neurovascular protection could be multifactorial, including increased NO to improve tissue perfusion [16,49,50]; yet, RIC therapy remains understudied in the animal models of comorbid stroke with impaired NOS3 activity, although the loss of NOS3 abolished the neuroprotective benefits of IC in mechanical IR models [18,46]; whether this loss of benefits was due to no effects on improving CBF remains unknown in thromboembolic stroke models, the most common type of strokes in humans [51]. The gene discussed is NOS3; the disease is stroke disorder.