Contraction of skeletal muscle during incidental movement compresses intramuscular arterioles and venules, and the resulting reactive hyperemia increases blood velocity through the conduit arteries, raising laminar shear stress on the endothelial glycocalyx.

Laminar shear stress is sensed by endothelial mechanoreceptors including PIEZO1 channels, integrins, and the glycocalyx, which trigger calcium influx and Akt/PI3K signaling that phosphorylate endothelial nitric oxide synthase at serine 1177.

Activated endothelial nitric oxide synthase converts L-arginine to nitric oxide, which diffuses into vascular smooth muscle and activates soluble guanylate cyclase, raising cyclic GMP and causing smooth muscle relaxation with reduced peripheral vascular resistance and lower resting blood pressure.

Contraction-induced calcium release and AMP-activated protein kinase activation drive GLUT4 translocation to the muscle sarcolemma, increasing insulin-independent glucose uptake, lowering fasting glucose and insulin concentrations, and reducing insulin resistance and advanced glycation end-product deposition in vessel walls.

Increased lipoprotein lipase activity in repeatedly contracting muscle hydrolyzes triglyceride-rich lipoproteins, lowering circulating triglycerides, raising HDL cholesterol, and reducing LDL particle retention and lipid deposition in the arterial intima.

Reduced visceral adipose mass and altered adipokine secretion lower circulating tumor necrosis factor-alpha, interleukin-6, and resistin, decreasing hepatic C-reactive protein production, monocyte recruitment, and macrophage foam-cell formation within atherosclerotic plaques.

Repeated submaximal cardiac work and reduced sympathetic outflow with increased vagal tone lower resting heart rate and myocardial oxygen demand, raise stroke volume, and stabilize myocardial electrical conduction, decreasing the occurrence of ventricular arrhythmia and sudden cardiac death.

The combined reduction in plaque lipid content, blood pressure, inflammatory signaling, and arrhythmic susceptibility decreases plaque rupture and occlusive thrombotic events, lowering the rate of major adverse cardiovascular events, cardiovascular death, and all-cause death.

The flattening of the dose-response curve at higher activity volumes occurs because endothelial nitric oxide production capacity, insulin-independent glucose transport, and lipoprotein lipase activity approach saturation, so additional contraction volume produces progressively smaller increments in vasodilation, glucose clearance, and lipid handling.