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 endothelial-specific KDR knockdown drastically reduced by 73% the portosystemic collateralization, and impaired the pathologic angiogenic potential of vascular endothelial cells at different levels (cell proliferation, sprouting and remodeling). Targeting endothelial KDR with therapeutic siRNAKDR-lipoplexes could be a promising and plausible treatment modality for attenuating the formation of portosystemic collaterals in a clinical setting.
Highlights
Portal hypertension is one of the most significant complications of chronic liver diseases, which represent serious threats to human health[1,2]
We found that siRNAKDR-lipoplex treatment reduced the expression of the recognized vascular remodeling markers[46,47,48], transforming growth factor-β (TGFβ, 64% decrease, p = 0.041) (Fig. 7C; full blots are shown in Supplementary Fig. S5A) and platelet-derived growth factor-B (PDGF-B; 57% decrease, p = 0.029) (Fig. 7D; full blots are shown in Supplementary Fig. S5B), in the portal vein of portal hypertensive mice
We have developed an innovative short interfering RNA (siRNA) delivery system based on clinical stage components, capable to efficiently and target Kinase insert domain receptor (KDR) in vascular endothelial cells in vivo by systemic intravenous administration
Summary
Portal hypertension is one of the most significant complications of chronic liver diseases, which represent serious threats to human health[1,2]. A major determinant of the severity of portal hypertension and liver disease is the development and maintenance of portosystemic collateral vessels, which include the gastroesophageal varices[3,4,5] These varices are fragile and prone to leak blood and even rupture, causing upper gastrointestinal tract bleeding. Hypertension but not in normal tissues, and has a central role in the regulation of portosystemic collateral development[6,7,8,9,10], and pathological angiogenesis[16,17,18,19,20], as we and other groups have previously demonstrated This means that KDR could be an excellent therapeutic target for portal hypertension and chronic liver disease[21,22,23]. Given the emerging roles of angiogenesis in a number of human pathologies, including inflammation, obesity and tumor growth, siRNAKDR-lipoplexes may provide a novel strategy to treat a wide spectrum of diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
