2008 George E. Brown Memorial Lecture—Flow-Induced Vasodilation in the Human Heart: Unique Endothelial Mechanisms and Clinical Insights

The most physiologically important stimulus for endothelium-dependent dilation is shear stress. Flow across the endothelial surface triggers a mechanochemical signal transduction pathway that results in release of nitric oxide (NO), prostacyclin, and/or endothelial-derived hyperpolarizing factors (EDHFs) such as hydrogen peroxide (H 2 O 2 ) and epoxyeicosatrienoic acid (EET). In most normal arteries, NO is the prominent mediator; however, in disease states, NO may be quenched by an elevation in superoxide. In these situations, compensatory dilator mechanisms may emerge, using EDHFs. One mechanism of this compensation may involve an important dilator pathway interaction whereby NO inhibits CYP450 monooxygenase. This is particularly prominent in the microcirculation, where disease-induced loss of NO often results in enhanced endothelial CYP450 activity and generation of EET as an alternate dilator. Recent data indicate that H 2 O 2 can also inhibit CYP450. In the human coronary microcirculation from subjects with coronary artery disease, NO and prostacyclin play little role in the dilation to most pharmacological agonists or to shear stress. Instead, EETs and H 2 O 2 are critical mediators of flow-induced dilation. Interestingly, the dilation requires ROS generation from the endothelial mitochondrial electron transport chain. Dual vessel bioassay studies suggest that H 2 O 2 is the transferable compound responsible for hyperpolarizing and relaxing the underlying vascular smooth muscle cells. In contrast, dilation to bradykinin also involves both H 2 O 2 and EET, but the H 2 O 2 originates from endothelial nicotinamide adenine dinucleotide phosphateoxidase oxidase, and EETs serve as an important transferable dilator agent. Endothelial release of NO, EET, and H 2 O 2 has implications beyond vasodilation. NO and EETs have potent antiatherosclerotic properties. Hydrogen peroxide, on the other hand, although a potent dilator, has proatherogenic properties. Therefore, it is hypothesized that the profile of endothelial factors released by shear stress and other stimuli may help determine the balance between proatherosclerotic and anti-atherosclerotic factors in vascular homeostasis.