Nitric oxide is a potent local vasodilator throughout the vasculature. It is first produced by endothelial cells and then diffuses through the tissue to smooth muscle cells, which act to dilate the vessel. The method by which nitric oxide (NO) is produced is of particular importance as failure to produce NO often results in arterial disease, such as hypertension. Additionally, NO has atheroprotective effects, shielding the vessel from plaque build-up resulting in blockage of flow. Our lab has conducted several studies to discover how the endothelial glycocalyx is the mechanotransducer for shear stress-induced nitric oxide production. We first observed how critical glycosaminoglycans (GAGs) in the glycocalyx are involved in this process (Figure 1).
These GAGs are known to associate with particular proteoglycans in the glycocalyx; heparin sulfate and chondroitin sulfate bind to syndecan-1, heparin sulfate alone binds to glypican-1, and hyaluranon binds to CD44). These associations as well as previous work modeling tip drag interactions spurred a recent study showing pertinent proteoglycans involved in shear-induced nitric oxide production (Figure 2).
Additionally, we are investigating the mechanism by which proteoglycans bind to the plasma membrane, which may influence shear-induced glycocalyx reorganization and signal transduction. We recently focused on proteoglycans, their associated GAGs, and two different kinds of membrane rafts: caveolae and lipid rafts. Our study shows how lipid rafts create mobility for the proteoglycan glypican-1 with shear stress (Figure 3). Caveolae have been shown by other authors to colocalize with eNOS, and are thereby involved in nitric oxide production.