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Glycocalyx Core Proteins Selectively Mediate Endothelial NOS activation and Cell Alignment in Response to Shear Stress

In this work, we clarified mechanisms by which the endothelial cell (EC) glycocalyx (GCX) mediates flow‐induced nitric oxide (NO) release and cell remodeling. We tested two hypotheses: (1) The glypican‐1 (GPC1) GCX core protein mediates flow‐induced EC NO synthase (eNOS) activation, because GPC1 is located in the caveolae where eNOS resides; and (2) The syndecan‐1 (SDC1) GCX core protein is involved in flow‐induced EC remodeling, because it has a cytoskeleton‐bound tail. EC monolayers with intact GCX, RNA‐silenced GPC1, or RNA‐silenced SDC1 were exposed to physiological shear stress for 3 to 24 hours. Shear‐conditioned EC with fully intact GCX exhibited eNOS activation in short‐term flow conditions and characteristic elongation and alignment in the direction of flow after long‐term exposure. GPC1 inhibition, not SDC1 reduction, blocked shear‐induced eNOS activation. EC remodeling in response to flow was attenuated in the absence of SDC1, but preserved with GPC1 knockdown. These findings provide evidence that the GCX GPC1 and SDC1 core proteins selectively mediate important endothelial cell responses to shear stress. Research support: 5T32HL007675, HL094889.