Microvascular dysfunction precedes the development of heart disease. Microvascular health can be assessed by determining the vasoactive, endothelial-derived mediator produced in response to increased flow that results in dilation (flow-induced dilation; FID). In isolated human arterioles, a healthy microvascular endothelium produces and dilates to the anti-inflammatory compound nitric oxide (NO), whereas a dysfunctional endothelium (e.g. vessels from patients with coronary artery disease; CAD) relies on the generation and utilization of hydrogen peroxide (H 2 O 2 ), a more inflammatory vasoactive mediator. We have previously shown that spingosine-1-phosphate (S1P), a biolipid shown to stimulate endothelial production of NO, is critical to maintain microvascular endothelial health. This sphingolipid has also been implicated in reducing cell senescence, a state of cell cycle arrest that promotes a highly oxidative environment. We hypothesized that microvessels from patients with CAD exhibit a higher amount of senescent endothelial cells and that treatment with S1P will improve microvascular endothelial dysfunction through endothelial cell senescence escape. Arterioles dissected from otherwise discarded surgical adipose specimens from adults with a clinical diagnosis of CAD were treated with S1P (1µM) or vehicle (methanol) for 20hrs in media. Pressure myography was used to measure the microvascular flow response and determine the endothelial-derived FID mediator. Endothelial cell senescence was assessed via immunofluorescence of the senescent marker p16. Vehicle-treated vessels from patients with CAD exhibited a reduction in FID in the presence of peg-catalase (%Maximum Dilation ± SEM, vehicle vs. vehicle + catalase, 74.6 ± 5.9% vs. -3.9 ± 2.2%, n=6 vs. n=6, respectively, p< 0.0001, two-way ANOVA) with no change in the presence of L-NAME (vehicle + L-NAME, 69.5± 4.9%, n=6, p=0.77, two-way ANOVA). Conversely, vessels from CAD patients treated with S1P had a reduction in FID in the presence of L-NAME (S1P vs. S1P + L-NAME, 80.6 ± 3.8% vs. 0.3± 2.0%, n=8 vs. n=8, respectively, p< 0.0001, two-way ANOVA) with no change in the presence of peg-catalase (S1P + catalase, 82.4 ± 5.4%, n=7, p=0.98, two-way ANOVA). These data indicate a transition in vasoactive mediator, from H 2 O 2 to NO following treatment with S1P. p16 was increased in microvessels from patients with CAD compared to otherwise healthy adults (Integrated Density of p16 ± SEM, non-CAD vs CAD, 6.9 ± 1 vs. 22.2 ± 4.5 n=5 vs. n=3 respectively, p=0.02 Mann-Whitney test). Vessels from CAD patients that were treated with S1P had a reduced expression of the senescent marker p16 (Integrated Density of p16/Number of Nuclei ± SEM, vehicle vs S1P, 70.2 ± 10.3 vs. 58.8 ± 7.5, n=5 vs. n=5, respectively, p=0.05, paired t-test). Together, these data imply that cell senescence plays a key role in microvascular endothelial dysfunction and S1P may serve as a potential therapeutic target to improve microvascular health. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Wannebo et al. (Fri,) studied this question.