Inflammation Journal

This review examines how structural injury to the endothelial glycocalyx is known to initiate the collapse of caveolin-1-dependent caveolae, and how this may influence the dysregulation of endothelin type B receptors. The glycocalyx, caveolae, and endothelin type B receptors are proposed to form an integrated mechanosensory axis that coordinates shear-dependent signaling, redox control, and endothelin peptide clearance. Under physiological flow conditions, heparan sulfate-mediated mechanotransduction is known to sustain caveolin-1 expression, which preserves caveolar organization, endothelial nitric oxide synthase coupling, and localization of endothelin type B receptors. Under disturbed flow or inflammatory stress, enzymatic shedding of the glycocalyx is associated with reduced caveolin-1 stability and subsequent disruption of caveolar microdomains. These structural alterations coincide with the uncoupling of endothelial nitric oxide synthase, increased reactive oxygen species generation, enhanced endothelin-1 transcription, and possibly the impaired localization of the endothelin type B receptors meant to clear endothelin-1 peptides. The combination of these processes suggests a potentially self-amplifying interaction between mechanotransductive failure, increased oxidative stress, and endothelin imbalance. The objective here is to reframe the current understanding of glycocalyx degradation and caveolar collapse as direct upstream contributors to endothelin type B receptor dysfunction, while simultaneously highlighting the preservation of this pathway as a potential therapeutic focus in vascular diseases such as hypertension and atherosclerosis. A stronger mechanistic definition of the relationship between glycocalyx degradation, caveolae destabilization, and altered endothelin type B receptor function is necessary to clarify how vascular injury may lead to persistent endothelial dysfunction. Future research in this area may present opportunities for therapeutic interventions focused on preservation or restoration of glycocalyx integrity and function and may allow interruption of the proposed pathological feedback loop responsible for these diseases, improving patient outcomes.