Simvastatin Preserves Human Microvascular Endothelial Barrier Function Through Mevalonate-Dependent Regulation of RhoB Localization and Activation
- 1Department of Pediatrics, Yale University, USA
Abstract
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.
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BibTeX
@misc{moralesmaldonado2026simvastatin,
title = {{Simvastatin Preserves Human Microvascular Endothelial Barrier Function Through Mevalonate-Dependent Regulation of RhoB Localization and Activation}},
author = {A. Morales-Maldonado and J. S. Pober and R. W. Pierce},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.762609},
url = {https://www.biorxiv.org/content/10.64898/2026.10.28.762609v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Simvastatin Preserves Human Microvascular Endothelial Barrier Function Through Mevalonate-Dependent Regulation of RhoB Localization and Activation
AU - A. Morales-Maldonado
AU - J. S. Pober
AU - R. W. Pierce
PY - 2026
DA - 2026/10/28
PB - bioRxiv
DO - 10.64898/2026.10.28.762609
UR - https://www.biorxiv.org/content/10.64898/2026.10.28.762609v1
AB - 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.
SN - 2692-8205
ER -