Sphingosine-1-Phosphate Promotes Resiliency to External Stress in the Human Microvasculature

Abstract

Exposure to external stress (e.g. high pressure, high glucose) promotes human microvascular endothelial dysfunction and reduces the overall magnitude of flow-induced dilation (FID). We have previously shown that treatment with sphingosine-1-phosphate (S1P), a sphingolipid known to activate pro-survival pathways in endothelial cells, restores nitric oxide (NO) as the primary mediator of flow-induced dilation (FID) in arterioles from patients with coronary artery disease. Whether pre-treatment with S1P can prevent stress-induced microvascular endothelial dysfunction remains unknown. Our hypothesis is that pre-conditioning with S1P will promote resiliency to external stress (high intraluminal pressure) and prevent stress-induced reduction of FID. Human resistance arterioles (100-250μm) from otherwise healthy adults (one risk factor or less for coronary artery disease) were dissected from discarded surgical adipose tissue and treated with S1P (1μM) or vehicle control for 16-20 hr prior to the flow experiment. Vessels were cannulated for videomicroscopy and stressed with elevated intraluminal pressure (150mmHg, 30 min) then pre-constricted with endothelin-1 prior to initiating flow to elicit dilation. Arterioles treated with vehicle and exposed to high intraluminal pressure exhibited an overall reduction in vasodilatory capacity to flow (37.3%±8.6) compared to non-stressed, vehicle treated microvessels (66.1%±5.5). However, the ability to dilate to flow was preserved in microvessels pre-treated with S1P and exposed to high pressure (74.8%±6.7) compared to vehicle and high pressure (37.3%±8.6). These data suggest that S1P-activated pathways may foster resilience by reversing stress-induced microvascular endothelial function. Targeting S1P signaling may offer a novel therapeutic strategy to prevent microvascular dysfunction and the myriad diseases it causes, such as large vessel atherosclerosis, and heart failure with preserved ejection fraction. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.