Abstract
Portal hypertension (PH) is a common complication and a leading cause of death in patients with chronic liver diseases. PH is underlined by structural and functional derangement of liver sinusoid vessels and its fenestrated endothelium. Because in most clinical settings PH is accompanied by parenchymal injury, it has been difficult to determine the precise role of microvascular perturbations in causing PH. Reasoning that Vascular Endothelial Growth Factor (VEGF) is required to maintain functional integrity of the hepatic microcirculation, we developed a transgenic mouse system for a liver-specific-, reversible VEGF inhibition. The system is based on conditional induction and de-induction of a VEGF decoy receptor that sequesters VEGF and preclude signaling. VEGF blockade results in sinusoidal endothelial cells (SECs) fenestrations closure and in accumulation and transformation of the normally quiescent hepatic stellate cells, i.e. provoking the two processes underlying sinusoidal capillarization. Importantly, sinusoidal capillarization was sufficient to cause PH and its typical sequela, ascites, splenomegaly and venous collateralization without inflicting parenchymal damage or fibrosis. Remarkably, these dramatic phenotypes were fully reversed within few days from lifting-off VEGF blockade and resultant re-opening of SECs' fenestrations. This study not only uncovered an indispensible role for VEGF in maintaining structure and function of mature SECs, but also highlights the vasculo-centric nature of PH pathogenesis. Unprecedented ability to rescue PH and its secondary manifestations via manipulating a single vascular factor may also be harnessed for examining the potential utility of de-capillarization treatment modalities.
Highlights
Different insults inflicting hepatocyte damage, such as alcohol or acute and chronic viral infections, may eventually lead to cirrhosis and intra-hepatic portal hypertension (PH)
We developed a transgenic system allowing for conditional suppression of endogenous Vascular Endothelial Growth Factor (VEGF) signaling, in the adult liver
Double transgenic mice were selected for VEGF modulations, whereas littermates that inherited only one of the two transgenes served as controls
Summary
Different insults inflicting hepatocyte damage, such as alcohol or acute and chronic viral infections, may eventually lead to cirrhosis and intra-hepatic portal hypertension (PH). Anatomical changes such as fibrotic scar and regenerative nodule formation that result in mechanical compression of the hepatic vasculature have been traditionally implicated as the dominant cause for increased intrahepatic vascular resistance, the hallmark of sinusoidal-type PH. It is acknowledged, that hepatic stellate cells (HSCs) play a pivotal role in this process. We have developed a unique transgenic mouse model for perturbing the hepatic vasculature in a conditional and reversible manner via manipulations of Vascular Endothelial Growth Factor (VEGF)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
