Knowledge of how this pathway can be maniuplated may lead to novel therapies for treatment and prevention of cardiovascular disease

Vasodilation to shear stress (flow-induced dilation; FID), is an endothelium-dependent process important for maintaining vascular homeostasis. We have previously shown that risk factors for, or the presence of coronary artery disease (CAD), evokes a transition in the endothelial mediator of FID from nitric oxide (NO) to mitochondrial-derived hydrogen peroxide (H2O2). Although both factors elicit smooth muscle relaxation, the non-vasomotor effects of each are generally opposite with NO stimulating anti-inflammatory, anti-thrombotic, and anti-proliferative pathways, compared to the pro-inflammatory, pro-thrombotic, and pro-atherogenic nature of H2O2.

Interestingly, sphingolipid metabolites can exert opposing effects on the endothelium. While ceramide is known to increase mitochondrial-derived ROS and promote inflammation, through a series of steps it can be converted to sphingosine-1-phosphate (S1P), a sphingolipid that has been shown to increase intracellular NO levels and maintain mitochondrial integrity. For instance, ceramide can be converted to sphingosine via neutral ceramidase (NCdase). Sphingosine can then undergo phosphorylation by sphingosine kinase to form S1P. The balance of these lipids, often referred to as the ‘sphingolipid rheostat’, can have a profound effect on cellular environment with the potential to influence the mediator of FID. For these reasons, knowledge of how this pathway can be manipulated may lead to novel therapies for treatment and prevention of cardiovascular disease.

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