title: Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats.
abstract: Pathological angiogenesis represents a critical hallmark for chronic liver diseases. Understanding the mechanisms regulating angiogenesis is essential to develop new therapeutic strategies that specifically target pathological angiogenesis without affecting physiological angiogenesis. Here we investigated the contribution and therapeutic impact of the endogenous angioinhibitor vasohibin-1 in portal hypertension and cirrhosis. The spatiotemporal expression profiling of vasohibin-1 and its relationship with vascular endothelial growth factor (VEGF), angiogenesis, and fibrogenesis was determined through the analysis of human cirrhotic liver specimens, widely accepted in vivo animal models of portal hypertension and cirrhosis, and in vitro angiogenesis assays. Effects of vasohibin-1 overexpression by adenoviral-mediated gene transfer on angiogenesis, fibrogenesis, and portal hypertension-associated hemodynamic alterations were also studied in rats. We found that vasohibin-1 and VEGF are up-regulated, in mesentery and liver, in cirrhotic and precirrhotic portal hypertensive rats and cirrhosis patients. Our results are consistent with vasohibin-1/VEGF cascades being spatially and temporally coordinated through a negative-feedback loop driving pathological angiogenesis. Paradoxically, further overexpression of vasohibin-1 by adenoviral gene transfer exerts multifold beneficial effects in portal hypertension and cirrhosis: reduction of pathologic angiogenesis, attenuation of liver fibrogenesis partly mediated through inhibition of hepatic stellate cell activation, and significant decreases in portocollateralization, splanchnic blood flow, portohepatic resistance, and portal pressure. The explanation for this apparent contradiction is that, unlike endogenous vasohibin-1, the ectopic overexpression is not regulated by VEGF and therefore disrupts the negative-feedback loop, thus generating constant, but lower levels of VEGF synthesis sufficient to maintain vascular homeostasis but not pathological angiogenesis.
  
  
  CONCLUSIONS
  Our study provides evidence that vasohibin-1 regulates portal hypertension-associated pathological angiogenesis and highlights that increasing vasohibin-1 might be a promising novel therapeutic strategy for portal hypertension and cirrhosis.
authors.affiliation: Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), CIBERehd, Hospital Clinic, University of Barcelona, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Coch
authors.forename: Marc
authors.initials: M
authors.lastname: Mejias
authors.forename: Annalisa
authors.initials: A
authors.lastname: Berzigotti
authors.forename: Ester
authors.initials: E
authors.lastname: Garcia-Pras
authors.forename: Javier
authors.initials: J
authors.lastname: Gallego
authors.forename: Jaime
authors.initials: J
authors.lastname: Bosch
authors.forename: Raul
authors.initials: R
authors.lastname: Mendez
authors.forename: Mercedes
authors.initials: M
authors.lastname: Fernandez
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D025461:Feedback, Physiological / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D006940:Hyperemia / Q000378:metabolism / Q000503:physiopathology; D006975:Hypertension, Portal / Q000378:metabolism / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C493181:VASH1 protein, human; C552060:VASH1 protein, rat; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat