Abbas Mohammed, Haddad Elizabeth, Hamer Mary, Nowrangi Derek, Zhang John, Pearce William J, Tang Jiping, Obenaus Andre
Department of Pediatrics, Loma Linda University, Loma Linda, CA, United States.
Department of Pediatrics, University of California, Irvine, Irvine, CA, United States.
Front Neurosci. 2020 Feb 4;14:46. doi: 10.3389/fnins.2020.00046. eCollection 2020.
Intracerebral hemorrhage (ICH) remains one of the most debilitating types of stroke and is characterized by a sudden bleeding from a ruptured blood vessel. ICH often results in high mortality and in survivors, permanent disability. Most studies have focused on neuroprotective strategies designed to minimize secondary consequences and prevent further pathology. Lacking is an understanding of how ICH acutely affects cerebrovascular components and their response to therapeutic interventions. We hypothesized that ICH alters cortical vessel complexity in the parenchyma adjacent to site of the initial vascular disruption and that vascular abnormalities would be mitigated by administration of the PDGFR inhibitor, Imatinib mesylate (Gleevec). Briefly, ICH was induced in male adult rats by injection of collagenase into basal ganglia, followed by Gleevec administration (60 mg/kg) 1 h after injury. Rats were then perfused using vessel painting methodology (Salehi et al., 2018b) to stain whole brain vascular networks at 1 day post-ICH. Axial and coronal wide field fluorescence microscopy was performed. Analyses for vascular features were undertaken and fractal analysis for vascular complexity. Data were collected from four groups of rats: Sham + Vehicle; Sham + Gleevec; ICH + Vehicle; ICH + Gleevec. Microscopy revealed that cortical vessels in both ipsi- and contralateral hemispheres exhibited significantly reduced density and branching by 22 and 34%, respectively. Fractal measures confirmed reduced complexity as well. Gleevec treatment further reduced vascular parameters, including reductions in vessel density in tissues adjacent to the ICH. The reductions in brain wide vascular networks after Gleevec in the current study after ICH is contrasted by previous reports of improved behavioral outcomes and decreased lCH lesion volumes Reductions in the vascular network after Gleevec may be involved in long-term repair mechanisms by pruning injured vessels to ultimately promote new vessel growth.
脑出血（ICH）仍然是最具致残性的中风类型之一，其特征是血管破裂导致突然出血。ICH常导致高死亡率，幸存者也会出现永久性残疾。大多数研究都集中在旨在将继发性后果降至最低并预防进一步病理变化的神经保护策略上。目前尚缺乏对ICH如何急性影响脑血管成分及其对治疗干预反应的了解。我们假设，ICH会改变初始血管破裂部位附近实质内的皮质血管复杂性，并且给予血小板衍生生长因子受体（PDGFR）抑制剂甲磺酸伊马替尼（格列卫）可减轻血管异常。简而言之，通过向雄性成年大鼠基底神经节注射胶原酶诱导ICH，然后在损伤后1小时给予格列卫（60mg/kg）。然后使用血管造影方法（Salehi等人，2018b）对大鼠进行灌注，以在ICH后1天对全脑血管网络进行染色。进行了轴向和冠状宽视野荧光显微镜检查。对血管特征进行了分析，并对血管复杂性进行了分形分析。数据收集自四组大鼠：假手术+赋形剂；假手术+格列卫；ICH+赋形剂；ICH+格列卫。显微镜检查显示，同侧和对侧半球的皮质血管密度和分支分别显著降低了22%和34%。分形测量也证实了复杂性降低。格列卫治疗进一步降低了血管参数，包括ICH附近组织中血管密度的降低。本研究中ICH后格列卫治疗后脑全血管网络的减少与先前关于行为结果改善和ICH病变体积减小的报道形成对比。格列卫治疗后血管网络的减少可能通过修剪受损血管以最终促进新血管生长而参与长期修复机制。
