Abstract
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.
Highlights
Spontaneous intracerebral hemorrhage (ICH) is defined as a sudden bleeding from ruptured cerebral blood vessels
The results are comprised of two components: (a) first we report the novel findings of how Intracerebral hemorrhage (ICH) impacts the cortical and basal ganglia vasculature following ICH, and (b) we describe the results of how Gleevec treatment after ICH may modify the cortical and basal ganglia vessels
This study for the first-time reports on quantitative measures of the vascular network within 24 h after ICH induction using a novel vessel painting methodology (Salehi et al, 2018b)
Summary
Spontaneous intracerebral hemorrhage (ICH) is defined as a sudden bleeding from ruptured cerebral blood vessels. The hemorrhagic expansion can be attributed to leakage or rebleeding from secondary mechanical shearing of vessels surrounding hematoma (Fisher, 1971) but other cellular processes are known to contribute including, but not limited to: (a) initiation by thrombin of the coagulation cascade leading to activated microglia (Wagner et al, 2002; Nakamura et al, 2005; Nakamura et al, 2006; Xi et al, 2006), (b) hematoma breakdown-products such as hemoglobin (Mracsko and Veltkamp, 2014), and (c) a robust inflammatory response (Wang and Dore, 2007; Yang et al, 2016) These secondary outcomes lead to a disrupted BBB resulting in significant brain edema (Hua et al, 2007) that are strongly predictive of functional outcomes (Gebel et al, 2002). A more complete understanding of how the vasculature is altered following ICH is warranted
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