Chodobski A, Chung I, Koźniewska E, Ivanenko T, Chang W, Harrington J F, Duncan J A, Szmydynger-Chodobska J
Department of Clinical Neurosciences, Brown University School of Medicine, Aldrich Building, Room 405, 593 Eddy Street, Providence, RI 02903, USA.
Neuroscience. 2003;122(4):853-67. doi: 10.1016/j.neuroscience.2003.08.055.
The formation of edema after traumatic brain injury (TBI) is in part associated with the disruption of the blood-brain barrier. However, the molecular and cellular mechanisms underlying these phenomena have not been fully understood. One possible factor involved in edema formation is vascular endothelial growth factor (VEGF). This growth factor has previously been demonstrated to increase the blood-brain barrier permeability to the low molecular weight markers and macromolecules. In this study, we analyzed the temporal changes in VEGF expression after TBI in rats. In the intact brain, VEGF was expressed at relatively low levels and was found in the cells located close to the cerebrospinal fluid space. These were the astrocytes located under the ependyma and the pia-glial lining, as well as the epithelial cells of the choroid plexus. In addition, several groups of neurons, including those located in the frontoparietal cortex and in all hippocampal regions, were VEGF-positive. The pattern of VEGF-immunopositive staining of neurons and choroidal epithelium suggested that in these cells, VEGF binds to the cell membrane-associated heparan sulfate proteoglycans. Following TBI, there was an early (within 4 h post-injury) increase in VEGF expression in the traumatized parenchyma associated with neutrophilic invasion. The ipsilateral choroid plexus appeared to play a role in facilitating the migration of neutrophils from blood into the cerebrospinal fluid space, from where many of these cells infiltrated the brain parenchyma. VEGF-immunopositive staining of neutrophils resembled haloes and was found ipsilaterally within the frontoparietal cortex and around the velum interpositum, a part of the subarachnoid space. These haloes likely represent the deposition of neutrophil-derived VEGF within the extracellular matrix, from where this growth factor may be gradually released during an early post-traumatic period. The maximum number of VEGF-secreting neutrophils was observed between 8 h and 1 day after TBI. In addition, from 4 h post-TBI, there was a progressive increase in the number of VEGF-immunoreactive astrocytes in the ipsilateral frontoparietal cortex. The maximum number of astrocytes expressing VEGF was observed 4 days after TBI, and then the levels of astroglial VEGF expression declined gradually. Early invasion of brain parenchyma by VEGF-secreting neutrophils together with a delayed increase in astrocytic synthesis of this growth factor correlate with the biphasic opening of the blood-brain barrier and formation of edema previously observed after TBI. Therefore, these findings suggest that VEGF plays an important role in promoting the formation of post-traumatic brain edema.
创伤性脑损伤（TBI）后水肿的形成部分与血脑屏障的破坏有关。然而，这些现象背后的分子和细胞机制尚未完全明确。血管内皮生长因子（VEGF）是参与水肿形成的一个可能因素。此前已证实这种生长因子可增加血脑屏障对低分子量标志物和大分子的通透性。在本研究中，我们分析了大鼠TBI后VEGF表达的时间变化。在完整的大脑中，VEGF以相对较低的水平表达，且在靠近脑脊液间隙的细胞中发现。这些细胞是室管膜下和软脑膜 - 胶质膜内衬的星形胶质细胞，以及脉络丛的上皮细胞。此外，几组神经元，包括位于额顶叶皮质和所有海马区域的神经元，VEGF呈阳性。神经元和脉络膜上皮细胞的VEGF免疫阳性染色模式表明，在这些细胞中，VEGF与细胞膜相关的硫酸乙酰肝素蛋白聚糖结合。TBI后，创伤实质内VEGF表达在早期（损伤后4小时内）增加，这与中性粒细胞浸润有关。同侧脉络丛似乎在促进中性粒细胞从血液迁移到脑脊液间隙中发挥作用，许多这些细胞从脑脊液间隙渗入脑实质。中性粒细胞的VEGF免疫阳性染色类似光环，并在额顶叶皮质同侧和蛛网膜下腔的一部分——中间帆周围被发现。这些光环可能代表中性粒细胞衍生的VEGF在细胞外基质中的沉积，在创伤后早期，这种生长因子可能从这里逐渐释放。在TBI后8小时至1天观察到分泌VEGF的中性粒细胞数量最多。此外，TBI后4小时起，同侧额顶叶皮质中VEGF免疫反应性星形胶质细胞的数量逐渐增加。在TBI后4天观察到表达VEGF的星形胶质细胞数量最多，然后星形胶质细胞VEGF表达水平逐渐下降。分泌VEGF的中性粒细胞早期侵入脑实质，以及该生长因子在星形胶质细胞合成中的延迟增加，与先前在TBI后观察到的血脑屏障双相开放和水肿形成相关。因此，这些发现表明VEGF在促进创伤后脑水肿的形成中起重要作用。
