The vascular endothelial glycocalyx is a dynamic gel layer composed of sulfated proteoglycans, hyaluronic acid, glycoproteins, etc. As a mechanical force sensor of the vascular endothelium, its integrity is crucial for maintaining vascular function. Low shear stress (<5 dyn/cm2) activates hyaluronidase 2 through an AMPK-mediated pathway, leading to the destruction of the glycocalyx; blood flow turbulence and pro-atherosclerotic shear stress waveforms can alter the distribution and synthesis of heparan sulfate and other components, exacerbating glycocalyx damage and promoting atherosclerosis. In addition, factors such as inflammation, oxidative stress, sepsis, and viruses jointly mediate glycocalyx depolymerization by regulating key degradative enzymes such as HYALs, HPSE, and MMPs. Currently, inhibitors targeting these enzymes (such as sulodexide and doxycycline) have shown protective potential. Future research needs to focus on the synergistic mechanism between biomechanics and degradative enzymes, and develop targeted intervention strategies to maintain vascular homeostasis and improve disease prognosis.