The somatostatin analogue octreotide inhibits angiogenesis in the earliest, but not in advanced, stages of portal hypertension in rats.
BACKGROUND
Angiogenesis is an important determinant of the pathophysiology of portal hypertension contributing to the formation of portosystemic collateral vessels and the hyperdynamic splanchnic circulation associated to this syndrome. Somatostatin and its analogues, like octreotide, have been shown to be powerful inhibitors of experimental angiogenesis.


OBJECTIVE
To determine whether octreotide has angioinhibitory effects in portal hypertensive rats.


METHODS
Partial portal vein-ligated (PPVL) rats were treated with octreotide or vehicle during 4 or 7 days. Splanchnic neovascularization and VEGF expression were determined by histological analysis and western blotting. Expression of the somatostatin receptor subtype 2 (SSTR2), which mediates the anti-angiogenic effects of octreotide, was also analyzed. Formation of portosystemic collaterals (radioactive microspheres) and hemodynamic parameters were also measured.


RESULTS
Octreotide treatment during 4 days markedly and significantly decreased splanchnic neovascularization, VEGF expression by 63% and portal pressure by 15%, whereas portosystemic collateralization and splanchnic blood flow were not modified. After 1 week of octreotide injection, portal pressure was reduced by 20%, but inhibition of angiogenesis escaped from octreotide therapy, a phenomenon that could be related to the finding that expression of SSTR2 receptor decreased progressively (up to 78% reduction) during the evolution of portal hypertension.


CONCLUSIONS
This study provides the first experimental evidence showing that octreotide may be an effective anti-angiogenic therapy early after induction of portal hypertension, but not in advanced stages most likely due to SSTR2 down-regulation during the progression of portal hypertension in rats. These findings shed light on new mechanisms of action of octreotide in portal hypertension.
Mejias
Marc
M
Hepatic Hemodynamic Laboratory, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Garcia-Pras
Ester
E
Tiani
Carolina
C
Bosch
Jaime
J
Fernandez
Mercedes
M
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D015282:Octreotide / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D017481:Receptors, Somatostatin; C115977:Sstr2 protein, rat; D042461:Vascular Endothelial Growth Factor A; D013004:Somatostatin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051547:Heme Oxygenase-1; D015282:Octreotide