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How to Say NO to Atherosclerosis

 


It is known that regular exercise may reduce the risk of atherosclerosis. The beneficial effect is mainly due to the shear stress (tangential force) on the vessel wall exerted by blood flow. The shear stress stimulates the production of nitric oxide (NO) from the endothelium lining the vessel wall. The endothelium-derived NO has anti-atherogenic properties. It may reduce platelet aggregation, prevent adhesion molecule expression, and inhibit both smooth muscle proliferation and endothelial cell apoptosis.

How could shear stress stimulate the production of NO? The detailed mechanism is not fully understood, but significant progress has been made in the past few years.

The most likely candidate for the mechanotransduction from shear stress to biochemical signal is integrins. It has been observed that RGD peptides that inhibit the binding of integrins avb3 and a5b1 to their ligands block the shear-induced vasodilation of coronary arteries (reference). Integrins are also known to induce the Src-Raf-MEK signaling pathway (review) which is involved in the shear-induced production of NO.

Shear stress may increase the production of NO via two mechanisms: (1) activation of the endothelial NO synthase (eNOS) leading to NO release immediately after the onset of shear stress and (2) stimulation of the expression of eNOS in the next several hours. The activation of eNOS is induced by the Src-VEGFR2-PI3K-Akt pathway which could be mediated by integrins (reference). The expression of eNOS is stimulated by the Src-Raf-MEK pathway (reference).

 

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