The effects of 5-fluorouracil chemotherapy on human microvascular endothelial function

Introduction: 5-fluorouracil (5FU) is one of the most commonly administered chemotherapies and is a key component of many gastrointestinal and head/neck cancer treatment regimens. Despite its clinical effectiveness, 5FU can result in the manifestation of severe chest pain in treated patients—presumably due to 5FU-induced vascular spasm. The onset of 5FU-induced chest pain not only poses immediate concern for the cardiovascular health of the patient but can also negatively impact cancer care if 5FU is contraindicated and ultimately replaced by a less effective treatment. As such, understanding how 5FU impacts cardiovascular function may have critical importance for continued use of this drug. To date, most research has focused on the effect of 5FU on large arteries, and less is known about its impact on the microcirculation. Given alterations in microvascular endothelial function are a known precursor to severe chest pain in other diseases, the objective of this study was to determine whether 5FU directly impairs human microvascular endothelial function. We hypothesized that ex vivo administration of 5FU would impair endothelium-dependent dilation to flow and acetylcholine (ACh) in human arterioles. Methods: Human adipose arterioles (mean max internal diameter: 157±45 µM) were dissected from fresh surgical discard tissue. Arterioles were canulated, pressurized, and allowed to equilibrate at 60 mmHg in a vessel chamber filled with physiological Krebs solution. Arterioles were then treated with a clinically relevant dose of 5FU (n=6, 500 µM) or volume matched Krebs buffer (n=3, CON) and allowed to equilibrate for 30 additional minutes. Endothelin-1 was used to preconstrict vessels, and endothelium-dependent dilation was assessed via videomicrocopy using 1) flow mediated dilation (FMD) at pressure gradients between 5 and 100 cmH2O and 2) increasing concentrations of ACh (10 -9 – 10 -4 M). Endothelium-independent dilation was assessed using papaverine (100 µM). Group differences in FMD and ACh were analyzed using 2-Way RM ANOVA with Šidák’s multiple comparison test whereas responses to papaverine were compared using independent-samples t-tests. All data are presented as a percentage of maximal diameter (mean±SD) and significance was set to p<0.05. Results: A significant pressure gradient x group interaction (p=0.008) was present for FMD indicating clear impairment in 5FU treated vessels compared to CON. Multiple comparisons revealed significantly reduced FMD in 5FU treated vessels at 50 cmH2O compared to CON (5FU: 25±36%; CON: 86±7%; p=0.04) while no differences were present at any other pressure gradients (all p>0.05). No significant dose x group interaction (p=0.06) or main effect for group (p=0.41) was present in response to ACh. However, there was a significant main effect for dose (p<0.001). No statistical differences were present between groups at individual doses of ACh despite a trend toward lower dilatory responses in 5FU treated vessels (all p>0.05). Papaverine-induced dilation was not different between groups (5FU: 90±8%; CON: 88±9%; p=0.67). Conclusion: These preliminary findings suggest that 5FU impairs endothelium-dependent dilation to flow, but not administration of ACh, in isolated human microvessels. Future work will seek to uncover the specific mechanistic dilatory pathways impacted by 5FU, with a long-term goal of establishing modalities to alleviate 5FU-induced vascular dysfunction. Funding for this project is supported by NIH grant T32 HL134643 and the Cardiovascular Center’s A.O. Smith Fellowship Scholars Program (STH) and R01HL173549 (AMB) This abstract was presented at the American Physiology Summit 2025 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.