NAD(P)H oxidase modulates angiogenesis and the development of portosystemic collaterals and splanchnic hyperaemia in portal hypertensive rats.
BACKGROUND
Recent studies have shown the presence of vascular endothelial growth factor (VEGF)-dependent splanchnic angiogenesis in experimental models of portal hypertension, and the role of such neovascularisation on the development of both portosystemic collaterals and hyperdynamic splanchnic circulation. However, the mechanisms modulating angiogenesis in portal hypertension are unknown. Experimental evidence indicates that NAD(P)H oxidase is required for VEGF-induced angiogenesis. Interestingly, we have recently shown that splanchnic NAD(P)H oxidase activity is significantly increased in portal hypertensive rats. Therefore, it could be possible that activated NAD(P)H oxidases modulate angiogenesis in portal hypertension.


OBJECTIVE
To determine the effects of chronic NAD(P)H oxidase inhibition on angiogenesis and splanchnic haemodynamics in portal hypertensive rats.


METHODS
Partial portal vein-ligated and sham-operated rats were treated with the NAD(P)H oxidase inhibitor apocynin, or with vehicle for 5 days. Then, the expression of angiogenesis markers (western blotting), the formation of portosystemic collaterals (radioactive microspheres) and the production of superoxide anion (lucigenin-enhanced chemiluminescence) were determined. Mean arterial pressure, portal pressure, and superior mesenteric arterial blood flow and resistance were also measured.


RESULTS
In portal hypertensive rats, NAD(P)H oxidase blockade significantly decreased portosystemic collateral formation, and superior mesenteric arterial flow. It also reduced the splanchnic expression of VEGF, VEGF receptor-2 and CD31, and attenuated the increased production of superoxide, compared with vehicle.


CONCLUSIONS
NAD(P)H oxidase plays an important role in experimental portal hypertension, modulating splanchnic angiogenesis, the formation of portosystemic collaterals and the development of splanchnic hyperdynamic circulation. These results suggest that NAD(P)H oxidase may represent a new target in the treatment of portal hypertension.
Angermayr
Bernhard
B
Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions, Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
Fernandez
Mercedes
M
Mejias
Marc
M
Gracia-Sancho
Jorge
J
Garcia-Pagan
Juan Carlos
JC
Bosch
Jaime
J
D000098:Acetophenones / Q000494:pharmacology; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003097:Collateral Circulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006940:Hyperemia / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D006975:Hypertension, Portal / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D017538:Mesenteric Artery, Superior / Q000503:physiopathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013152:Splanchnic Circulation / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
D000098:Acetophenones; D043925:Angiogenesis Inducing Agents; D004791:Enzyme Inhibitors; D013481:Superoxides; C056165:acetovanillone; D019255:NADPH Oxidases