Pierce, R. W. | bioRxiv Science

bioRxiv2026

Simvastatin Preserves Human Microvascular Endothelial Barrier Function Through Mevalonate-Dependent Regulation of RhoB Localization and Activation

Endothelial barrier failure contributes to edema, tissue hypoperfusion, and organ dysfunction during inflammatory critical illness. RhoB has emerged as a regulator of tight junction disruption in human microvascular endothelial cells, but whether clinically used drugs can modulate RhoB-dependent barrier failure remains unclear. We tested whether simvastatin preserves human dermal microvascular endothelial cell barrier function during TNF stimulation and examined the role of mevalonate-dependent RhoB localization and activation. Simvastatin pretreatment attenuated TNF-induced loss of transendothelial electrical resistance and preserved junctional ZO-1 and claudin-5 organization. Simvastatin reduced membrane-associated and increased nuclear RhoB, decreased active RhoB, and suppressed myosin light chain phosphorylation. RhoB silencing phenocopied the barrier-protective effect of simvastatin, and combined RhoB silencing and simvastatin did not provide additive protection. Mevalonate supplementation reversed simvastatin-mediated preservation of barrier function, restored peripheral RhoB localization, and restored MLC phosphorylation. These findings identify mevalonate-dependent RhoB spatial regulation as a statin-sensitive mechanism contributing to inflammatory microvascular barrier dysfunction.

cell biology↗

bioRxiv2026

Oncostatin M-driven leak in human endothelial cells with preserved tight junctions

Blood vessels must preserve blood volume while permitting exchange of nutrients. Endothelial cells line the lumen of all blood vessels and form the intercellular junctions that govern vascular permeability. In acute critical illness the barrier fails, fluid escapes into tissues, and the resulting loss of volume and impaired nutrient exchange cause organ failure. Several inflammatory cytokines are known to disrupt junctions in cultured cells, yet therapies targeting these models have failed. How blood vessels respond to critical illness has remained largely elusive because endothelial cells are generally inaccessible. Here we profile endothelial cells recovered directly from critically ill children to show that oncostatin M drives a previously unrecognized mode of vascular leak. Oncostatin M increases permeability by forming narrow, nanoscale channels within the overlapping borders of adjacent cells, around intact tight junctions. These channels permit passage of small and intermediate sized solutes. Their formation depends on non-canonical signaling in which the kinase JAK1 activates two required parallel pathways (via ERK1 and AKT1) that converge on the transcription factor c-Fos. Inhibiting JAK1, either parallel pathway or depleting c-Fos, prevents oncostatin M-induced loss of barrier function. These results identify a permeability mechanism distinct from the junction disassembly driven by the cytokines that have dominated this field and implicate kinases already targeted by approved drugs as potential points of intervention. More broadly, vascular barriers are transiently loosened during immune-cell trafficking and metastasis, raising the possibility that diverse forms of vascular permeability arise through regulated nanoscale remodeling rather than junctional breakdown.

cell biology↗