Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats
Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats
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DOI：
10.1002/hep.21785
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发表时间：
2007-10-01
期刊：
影响因子：
13.5
通讯作者：
Bosch, Jaime
中科院分区：
文献类型：
--
作者：
Fernandez, Mercedes;Mejias, Marc;Bosch, Jaime
血管内皮生长因子（VEGF）和血小板源性生长因子（PDGF）途径对血管生成至关重要，血管生成是门静脉高压症发病机制的重要组成部分。本研究确定了抑制VEGF和/或PDGF信号传导对完全建立的门静脉高压症大鼠的高动力内脏循环和门体动脉侧支化的影响，从而模拟患者的情况。门静脉结扎大鼠接受雷帕霉素（VEGF信号抑制剂），格列卫（PDGF信号抑制剂），或同时当门静脉高压症已经完全发展。血流动力学研究采用渡越时间血流仪。放射性微球测量门体侧支循环的范围。Western blotting和免疫组化检测血管生成介质的表达。VEGF和PDGF信号传导的组合抑制显著减少内脏新血管形成（即，CD 31和VEGFR-2表达）和新生血管周细胞覆盖率（即，α-平滑肌肌动蛋白和PDGFR-β表达）并转化为血液动力学效应，其标记为门静脉压力降低40%、上级肠系膜动脉血流降低30%和上级肠系膜动脉阻力增加63%，从而显著逆转大鼠门脉高压引起的血流动力学变化。门体侧支化也减少。结论我们的研究结果提供了新的见解，血管生成如何调节门静脉高压症的维持门静脉压力增加，高动力循环，内脏新生血管，和门体支循环的VEGF和PDGF调节。重要的是，这些发现还表明，扩展的抗血管生成策略（即靶向VEGF/内皮细胞和PDGF/周细胞）可能是治疗门静脉高压症的新方法。
Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) pathways are crucial to angiogenesis, a process that contributes significantly to the pathogenesis of portal hypertension. This study determined the effects of inhibition of VEGF and/or PDGF signaling on hyperdynamic splanchnic circulation and portosystemic collateralization in rats with completely established portal hypertension, thus mimicking the situation in patients. Portal vein-ligated rats were treated with rapamycin (VEGF signaling inhibitor), Gleevec (PDGF signaling inhibitor), or both simultaneously when portal hypertension was already fully developed. Hemodynamic studies were performed by transit-time flowmetry. The extent of portosystemic collaterals was measured by radioactive microspheres. The expression of angiogenesis mediators was determined by Western blotting and immunohistochemistry. Combined inhibition of VEGF and PDGF signaling significantly reduced splanchnic neovascularization (i.e., CD31 and VEGFR-2 expression) and pericyte coverage of neovessels (that is, a-smooth muscle actin and PDGFR-beta expression) and translated into hemodynamic effects as marked as a 40% decrease in portal pressure, a 30% decrease in superior mesenteric artery blood flow, and a 63% increase in superior mesenteric artery resistance, yielding a significant reversal of the hemodynamic changes provoked by portal hypertension in rats. Portosystemic collateralization was reduced as well. Conclusions Our results provide new insights into how angiogenesis regulates portal hypertension by demonstrating that the maintenance of increased portal pressure, hyperkinetic circulation, splanchnic neovascularization, and portosystemic collateralization is regulated by VEGF and PDGF in portal hypertensive rats. Importantly, these findings also suggest that an extended antiangiogenic strategy (that is, targeting VEGF/endothelium and PDGF/pericytes) may be a novel approach to the treatment of portal hypertension.