Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension.
OBJECTIVE
Angiogenesis is a pathological hallmark of portal hypertension. Although VEGF is considered to be the most important proangiogenic factor in neoangiogenesis, this process requires the coordinated action of a variety of factors. Identification of novel molecules involved in angiogenesis is highly relevant, since they may represent potential new targets to suppress pathological neovascularization in angiogenesis-related diseases like portal hypertension. The apelin/APJ signaling pathway plays a crucial role in angiogenesis. Therefore, we determined whether the apelin system modulates angiogenesis-driven processes in portal hypertension.


METHODS
Partial portal vein-ligated rats were treated with the APJ antagonist F13A for seven days. Splanchnic neovascularization and expression of angiogenesis mediators (Western blotting) was determined. Portosystemic collateral formation (microspheres), and hemodynamic parameters (flowmetry) were also assessed.


RESULTS
Apelin and its receptor APJ were overexpressed in the splanchnic vasculature of portal hypertensive rats. F13A effectively decreased, by 52%, splanchnic neovascularization and expression of proangiogenic factors VEGF, PDGF and angiopoietin-2 in portal hypertensive rats. F13A also reduced, by 35%, the formation of portosystemic collateral vessels.


CONCLUSIONS
This study provides the first experimental evidence showing that the apelin/APJ system contributes to portosystemic collateralization and splanchnic neovascularization in portal hypertensive rats, presenting a potential novel therapeutic target for portal hypertension.
Tiani
Carolina
C
Hepatic Hemodynamic Laboratory, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Ciberehd, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain.
Garcia-Pras
Ester
E
Mejias
Marc
M
de Gottardi
Andrea
A
Berzigotti
Annalisa
A
Bosch
Jaime
J
Fernandez
Mercedes
M
D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D003097:Collateral Circulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D006975:Hypertension, Portal / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D018994:Myosin Light Chains / Q000235:genetics; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D010766:Phosphorylation; D011168:Portal System / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000235:genetics / Q000502:physiology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013152:Splanchnic Circulation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000073861:Apelin; D000075244:Apelin Receptors; C498579:Apln protein, rat; C491284:Aplnr protein, rat; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D018994:Myosin Light Chains; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D052250:Nitric Oxide Synthase Type III; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048049:Extracellular Signal-Regulated MAP Kinases