BackgroundSepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics.PCSK9loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults. In contrast, we have previously demonstrated higher mortality in the juvenile host. Given the potential pleiotropic effects of PCSK9 on the endothelium, beyond canonical effects on serum lipoproteins, both of which may influence sepsis outcomes, we sought to test the influence ofPCSK9LOF genotype on endothelial dysfunction.MethodsSecondary analyses of a prospective observational cohort of pediatric septic shock. Genetic variants ofPCSK9andLDLRgenes, serum PCSK9, and lipoprotein concentrations were determined previously. Endothelial dysfunction markers were measured in day 1 serum. We conducted multivariable linear regression to test the influence ofPCSK9LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses to test impact of select endothelial markers on the association betweenPCSK9LOF genotype and mortality. JuvenilePcsk9null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified.ResultsA total of 474 patients were included.PCSK9LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of those homozygous for the rs688LDLRvariant that renders it insensitive to PCSK9. Serum PCSK9 was not correlated with endothelial dysfunction.PCSK9LOF influenced concentrations of Angiopoietin-1 (Angpt-1) upon adjusting for potential confounders including lipoprotein concentrations, with false discovery adjusted p value of 0.042 and 0.013 for models that included LDL and HDL, respectively. Causal mediation analysis demonstrated that the effect ofPCSK9LOF on mortality was mediated by Angpt-1 (p= 0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype.ConclusionsWe present genetic and biomarker association data that suggest a potential direct role of the PCSK9-LDLR pathway on Angpt-1 in the developing host with septic shock and warrant external validation. Further, mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of pediatric-specific sepsis therapies.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s13054-023-04535-1.