Therapeutic siRNA targeting endothelial KDR decreases portosystemic collateralization in portal hypertension.

Scientific Reports
Javier GallegoMercedes Fernandez

Abstract

Development of portosystemic collateral vessels and gastroesophageal varices is responsible for the most serious clinical consequences of portal hypertension, but effective clinical therapies are limited. Here we developed and investigated the therapeutic potential of an innovative liposomally-formulated short-interfering RNA (siRNA) technology based on clinical stage components, capable to attenuate production of the endothelial kinase insert domain receptor (KDR), which controls portosystemic collateralization and contributes to disease progression and aggravation. These siRNAs were first validated in vitro, and then, their therapeutic potential on portosystemic collateralization and pathological angiogenesis was tested in vivo in mouse models of portal hypertension (portal vein-ligation). siRNAKDR-lipoplexes efficiently transported siRNAKDR to vascular endothelial cells in mesenteric microvenules and portal vein of portal hypertensive mice, where collaterogenesis and angiogenesis take place. This systemic treatment significantly downregulated pathological KDR overexpression, without causing complete KDR knockout, preserving homeostatic baseline KDR levels and thus limiting adverse effects. siRNAKDR-lipoplex-induced endotheli...Continue Reading

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Citations

Jan 11, 2020·Frontiers in Immunology·Marta Ramirez-Pedraza, Mercedes Fernández
Mar 20, 2020·International Journal of Molecular Sciences·Sandra TorresJonel Trebicka

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Methods Mentioned

BETA
transfection
PCR
transfections
dynamic light scattering
fluorescence microscopy
confocal microscopy
Knockdown

Software Mentioned

Imaging ProPlus
IPLab
ADI Chart
AxioVision
Image J

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