Adaptor protein p66(Shc) mediates hypertension-associated, cyclic stretch-dependent, endothelial damage.

Increased cyclic stretch to the vessel wall, as observed in hypertension, leads to endothelial dysfunction through increased free radical production and reduced nitric oxide bioavailability. Genetic deletion of the adaptor protein p66 Shc protects mice against age-related and hyperglycemia-induced endothelial dysfunction, as well as atherosclerosis and stroke. Furthermore, p66 Shc mediates vascular dysfunction in hypertensive mice. However, the direct role of p66 Shc in mediating mechanical force–induced free radical production is unknown; thus, we studied the effect of cyclic stretch on p66 Shc activation in primary human aortic endothelial cells and aortic endothelial cells isolated from normotensive and hypertensive rats. Exposure of human aortic endothelial cells to cyclic stretch led to a stretch- and time-dependent p66 Shc phosphorylation at Ser36 downstream of integrin α5β1 and c-Jun N-terminal kinase. In parallel, nicotinamide adenine dinucleotide phosphate oxidase activation, as well as production of reactive oxygen species, increased, whereas nitric oxide bioavailability decreased. Silencing of p66 Shc blunted stretch-increased superoxide anion production and nicotinamide adenine dinucleotide phosphate oxidase activation and restored nitric oxide bioavailability. In line with the above, activation of p66 Shc increased in isolated aortic endothelial cells of spontaneously hypertensive rats compared with normotensive ones. Pathological stretch by activating integrin α5β1 and c-Jun N-terminal kinase phosphorylates p66 Shc at Ser36, augments reactive oxygen species production via nicotinamide adenine dinucleotide phosphate oxidase, and in turn reduces nitric oxide bioavailability. This novel molecular pathway may be relevant for endothelial dysfunction and vascular disease in hypertension.