Co-therapy with S1P and heparan sulfate derivatives to restore endothelial glycocalyx and combat pro-atherosclerotic...

Endothelial cell (EC) glycocalyx (GCX) shedding from disturbed blood flow and chemical factors leads to low-density lipoprotein infiltration, reduced nitric oxide synthesis, vascular dysfunction and atherosclerosis. This study evaluates a therapy combining sphingosine-1-phosphate (S1P) and heparin (heparan sulfate derivative). We hypothesized that heparin/S1P co-treatment repairs mechanically damaged EC GCX in disturbed flow (DF) regions and restores anti-atherosclerotic mechanotransduction to treat cardiovascular disease.

We used a parallel-plate flow chamber to simulate flow conditions in vitro and a partial carotid ligation mouse model to mimic DF in vivo. Heparin and albumin-bound S1P were administered to assess their reparative effects on the endothelial GCX. Fluorescent staining, confocal microscopy, and ultrasound evaluated endothelial cell function and endothelial-dependent vascular function. Barrier functionality was assessed via macrophage uptake. Heparin/S1P mechanism-of-action insights were gained through fluid dynamics simulations and staining of GCX synthesis enzyme and S1P receptor. Statistical analyses validated the results.

The in vitro data showed that heparin/S1P therapy improves DF-conditioned ECs by restoring GCX and elevating vasodilator eNOS (endothelial-type nitric oxide synthase) expression. In vivo studies confirmed GCX degradation, vessel inflammation, hyperpermeability, and wall thickening in the mouse model's partially ligated left carotid artery. Heparin/S1P treatment restored GCX thickness and coverage, reduced inflammation and hyperpermeability, and inhibited vessel wall thickening.

This work introduces a new approach to regenerating the EC GCX and restoring its function in ECs under DF conditions, offering a groundbreaking solution for preventing cardiovascular diseases like atherosclerosis.