Buschmann Ivo R, Busch Hans-Jörg, Mies Günter, Hossmann Konstantin-Alexander
Albert Ludwigs University, Research Group for Experimental and Clinical Arteriogenesis, Department for Cardiology and Angiology, Breisacher Strasse 66, Freiburg im Breisgau, Germany.
Circulation. 2003 Aug 5;108(5):610-5. doi: 10.1161/01.CIR.0000074209.17561.99. Epub 2003 Jun 30.
Colony-stimulating factors (CSFs) have been shown to effectively induce arteriogenesis in the hindlimb. Moreover, clinical trials demonstrated positive effects of CSFs on arteriogenesis in patients with coronary artery disease. However, patients with cerebrovascular disease have not yet profited from treatments aimed at the growth of brain vessels. Thus far, angiogenesis studies have failed to demonstrate improvement of stroke outcome. Arteriogenesis differs from angiogenesis in that it substitutes arterial collaterals for the occluded artery.
We tested in a novel brain arteriogenesis rat model (occlusion of vertebral plus left carotid artery [3-VO]) the application of CSFs or saline over 7 or 21 days. On 3-VO postmortem, latex perfusion demonstrated a time- and treatment-dependent arteriogenesis of the posterior cerebral artery (PCA). In saline-treated animals, the PCA diameter increased by 39%; in granulocyte-macrophage (GM)-CSF-treated animals, this increase was significantly faster (72% after 1 week). Functionally, saline-treated animals exhibited a decline of CO2 reactivity (mm Hg) from 1.48% to 0.1% compared with GM-CSF-treated animals (1.43% arterial pCo2 change after 1 week). This difference remained significant after 3 weeks. This functional improvement correlated with increased numbers of CD68-positive macrophages in histological sections of the PCA in GM-CSF--treated animals and only a few macrophages in saline-treated animals.
To the best of our knowledge, this is the first report of stimulation of arteriogenesis in the brain. The subcutaneous application of GM-CSF led to functional improvement of brain hemodynamic parameters.
集落刺激因子（CSF）已被证明能有效诱导后肢动脉生成。此外，临床试验表明CSF对冠状动脉疾病患者的动脉生成有积极作用。然而，脑血管疾病患者尚未从旨在促进脑血管生长的治疗中获益。迄今为止，血管生成研究未能证明中风预后得到改善。动脉生成与血管生成的不同之处在于，它用动脉侧支替代闭塞的动脉。
我们在一种新型的脑动脉生成大鼠模型（椎动脉加左颈动脉闭塞[3-VO]）中，测试了在7天或21天内应用CSF或生理盐水的效果。在3-VO模型大鼠死后，乳胶灌注显示大脑后动脉（PCA）的动脉生成具有时间和治疗依赖性。在生理盐水处理的动物中，PCA直径增加了39%；在粒细胞-巨噬细胞（GM）-CSF处理的动物中，这种增加明显更快（1周后增加72%）。在功能上，与GM-CSF处理的动物相比（1周后动脉血二氧化碳分压变化1.43%），生理盐水处理的动物二氧化碳反应性（mmHg）从1.48%下降到0.1%。3周后这种差异仍然显著。这种功能改善与GM-CSF处理的动物PCA组织切片中CD68阳性巨噬细胞数量增加以及生理盐水处理的动物中仅有少量巨噬细胞有关。
据我们所知，这是关于大脑中动脉生成刺激的首次报道。皮下应用GM-CSF导致脑血流动力学参数的功能改善。
