Inhibition of vascular endothelial growth factor receptor 2 activity in experimental brain contusions aggravates injury outcome and leads to early increased neuronal and glial degeneration
Inhibition of vascular endothelial growth factor receptor 2 activity in experimental brain contusions aggravates injury outcome and leads to early increased neuronal and glial degeneration
复制标题
DOI：
10.1111/j.1460-9568.2005.04527.x
复制
发表时间：
2006-01-01
影响因子：
3.4
通讯作者：
Holmin, S
中科院分区：
文献类型：
--
作者：
Sköld, MK;Risling, M;Holmin, S
创伤性脑损伤(TBI)后的血管生成可能对创伤后修复过程和继发性损伤的发展具有重要意义。血管内皮生长因子(VEGF)是内皮细胞增殖、血管生成和血管通透性的主要调节因子，其受体(VEGFR1和VEGF2)在大鼠脑损伤后有表达。在目前的工作中，我们试图通过特异性的VEGFR2活性抑制来进一步阐明血管内皮生长因子在脑创伤后的作用。在接受VEGFR2阻断的大鼠中，我们报告了出血面积的增加(P<；0.05)，神经损伤标志物神经元特异烯醇化酶(P<；0.05)和神经胶质损伤标志物S100β(P<；0.05)的早期水平增加，以及末端脱氧核苷酸转移酶介导的脱氧尿嘧啶核苷-生物素缺口末端标记-(TUNEL-)和荧光翡翠B-(P<；0.05)阳性细胞的数量增加，所有这些都在已知的VEGF/VEGFR血管反应之前增加。通过微管相关蛋白2表达减少(P<；0.05)和胶质纤维酸性蛋白反应性增加(P<；0.05)，也可以显示损伤面积的增加。此外，通过von Willebrandt因子阳性细胞测量的血管密度降低(P<；0.05)。通过巨噬细胞、粒细胞和细胞内黏附分子的染色测量，两组之间在创伤后炎症反应方面没有差异。综上所述，我们的研究结果表明，在脑损伤后，VEGF/VEGFR2的上调是脑损伤的一个重要的内源性细胞保护机制。文中还讨论了血管内皮生长因子在脑外伤后神经血管单位的血管、神经元和神经胶质细胞中的可能作用。
Angiogenesis following traumatic brain injuries (TBIs) may be of importance for post-traumatic reparative processes and the development of secondary injuries. We have previously shown expression of vascular endothelial growth factor (VEGF), a major regulator of endothelial cell proliferation, angiogenesis and vascular permeability, and VEGF receptors (VEGFR1 and 2) after TBI in rat. In the present work we tried to further elucidate the role of VEGF after TBI by performing specific VEGFR2 activity inhibition. In rats subjected to VEGFR2 blockage we report an increased haemorrhagic area (P < 0.05), early increase in serum levels of neural injury marker neuron-specific enolase (P < 0.05) and glial injury marker S100 beta (P < 0.05), and increased numbers of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling- (TUNEL-) and FluoroJade B- (P < 0.05) positive cells, all increases preceding the known VEGF/VEGFR vascular response in brain trauma. An increase in lesion area, as measured by decreased microtubuli-associated protein 2 expression (P < 0.05) and increased glial fibrillary acidic protein reactivity (P < 0.05), could also be demonstrated. In addition, vascular density, as measured by von Willebrandt factor-positive cells, was decreased (P < 0.05). No differences in post-traumatic inflammatory response, as measured by stainings for macrophages, granulocytes and intracellular adhesion molecules, were shown between the groups. Taken together, our findings point towards VEGF/VEGFR2 up-regulation after TBI as being an important endogenous cytoprotective mechanism in TBI. The possible importance of VEGF on the vascular, neuronal and glial compartments of the neurovascular unit after TBI is discussed.