The somatostatin analogue octreotide inhibits angiogenesis in the earliest, but not in advanced, stages of portal hypertension in rats.
The somatostatin analogue octreotide inhibits angiogenesis in the earliest, but not in advanced, stages of portal hypertension in rats.
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DOI：
10.1111/j.1582-4934.2008.00218.x
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发表时间：
2008-09
影响因子：
5.3
通讯作者：
Fernandez M
中科院分区：
文献类型：
--
作者：
Mejias M;Garcia-Pras E;Tiani C;Bosch J;Fernandez M
背景资料：血管生成是门静脉高压症病理生理学的重要决定因素，有助于形成门体侧支血管和与该综合征相关的高动力内脏循环。生长抑素及其类似物，如奥曲肽，已被证明是实验性血管生成的强效抑制剂。目的：探讨奥曲肽对门脉高压大鼠的血管生成是否有抑制作用。方法：部分门静脉结扎（PPVL）大鼠分别给予奥曲肽或溶媒治疗4天或7天。通过组织学分析和蛋白质印迹法测定内脏新生血管和VEGF表达。生长抑素受体亚型2（SSTR 2），介导的奥曲肽的抗血管生成作用的表达，也进行了分析。还测量了门体侧支循环（放射性微球）的形成和血流动力学参数。结果如下：奥曲肽治疗4天期间，内脏新血管形成，VEGF表达显着下降63%，门静脉压力下降15%，而门体动脉侧支化和内脏血流量没有改变。奥曲肽注射1周后，门静脉压力降低了20%，但奥曲肽治疗未能抑制血管生成，这一现象可能与门静脉高压演变过程中SSTR 2受体表达进行性降低（降低高达78%）有关。结论：这项研究提供了第一个实验证据，表明奥曲肽可能是一种有效的抗血管生成治疗诱导门静脉高压症后早期，但不是在晚期阶段，最有可能是由于SSTR 2下调在大鼠门静脉高压症的进展。这些发现揭示了奥曲肽治疗门静脉高压症的新作用机制。
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. Aim: 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. Conclusion: 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.
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影响因子：
13.5
作者：
CIRERA, I;FEU, F;RODES, J
通讯作者：
RODES, J
影响因子：
13.5
作者：
Fernandez, Mercedes;Mejias, Marc;Bosch, Jaime
通讯作者：
Bosch, Jaime
影响因子：
25.7
作者：
Fernandez, M;Lambrecht, RW;Bonkovsky, HL
通讯作者：
Bonkovsky, HL
影响因子：
7.3
作者：
Fernandez, M;Bonkovsky, HL
通讯作者：
Bonkovsky, HL
影响因子：
3
作者：
Abbasoglu, Semra Dogru;Erbil, Yesim;Toker, Gulcin
通讯作者：
Toker, Gulcin