Nitric oxide (NO) toxicity is in part mediated by generation of
peroxynitrite with concomitant production of
superoxide under pathological brain conditions such as
ischemia and
Alzheimer's disease. The pathophysiological relevance of
endothelial nitric oxide synthase (eNOS) to
brain embolism-induced neurovascular injury has not been documented. We found that
microsphere embolism (ME)-induced aberrant eNOS expression in vascular endothelial cells likely mediates blood-brain barrier (BBB) disruption via
peroxynitrite formation and in turn causes
brain edema. We also demonstrated that a mild ME model was useful for investigating the sequential events of neurovascular injury followed by
beta-amyloid accumulation and tau hyperphosphorylation. Indeed, immunoblotting of purified brain microvessels revealed that
beta-amyloid accumulation significantly increased one week after ME induction and remained elevated for twelve weeks in those animals. Moreover, we also confirmed that
peroxynitrite formation and eNOS uncoupling-mediated
superoxide generation in microvessels are inhibited by a novel
calmodulin inhibitor. Thus,
peroxynitrite formation via elevated eNOS is associated with endothelial cell injury with concomitant
beta-amyloid accumulation in microvessels of aged rats. In this review, we focus on the detrimental effects of eNOS expression following
brain embolism and introduce an attractive model representing progressive
Alzheimer's disease pathology in brain.