Cerebral micro hemorrhages (CMH), the microscopic manifestations of cerebral microbleeds (CMB), are characterized by the accumulation of blood degradation products within the brain. Detection of CMH involves magnetic resonance imaging (MRI) identification of ferromagnetic iron and histological examination using Prussian blue staining, which reveals hemosiderin-iron.
CMH is frequently observed in various health conditions, including hypertension, cerebral amyloid angiopathy, Alzheimer’s disease, chronic kidney disease, cerebrovascular disease, and the natural aging process. Age emerges as a pivotal independent risk factor for CMB, with an escalating prevalence of CMB in older populations.
Importantly, CMB is linked to an elevated risk of both ischemic and haemorrhagic stroke, cognitive decline, and dementia. This association underscores the growing clinical relevance of CMB in aging populations. In a study exploring the dynamics of CMH development, red blood cells (RBC) were subjected to oxidative stress using tert-butylhydroperoxide (t-BHP), fluorescently labelled, and introduced into adult Tie2-GFP mice.
Employing in vivo two-photon imaging and ex vivo confocal microscopy, the researchers sought to understand the temporal profile of RBC–brain endothelial interactions associated with oxidatively stressed RBC. The investigation extended to examining their relationship with microglial activation and CMH through post-mortem histology.
The findings revealed a significant and rapid stalling of oxidatively stressed RBC in cerebral vessels in mice, accompanied by a decrease in blood flow velocity. Notably, this reduction in blood flow recovered after 5 days. Post-mortem histological analysis confirmed significantly increased interactions between RBC and cerebral endothelium, as well as heightened microglial activation at 24 hours post t-BHP-treated RBC injection, persisting at 7 days.
Intriguingly, significant CMH developed without detectable blood–brain barrier (BBB) leakage after t-BHP-RBC injection. The results of the study indicate that RBC damaged by oxidative stress associate with brain capillary endothelium. These altered RBC–brain capillary endothelial interactions, characterized by RBC stalls, are dynamic and resolve over time as RBC extravasate into the brain parenchyma.
Importantly, these modified interactions coincide with a reduction in cerebral blood flow velocity, persistent microglial activation, and an increased load of CMH in the absence of overt BBB leakage. This research challenges the traditional perspective on CMH development, which predominantly attributes it to RBC extravasation in brain parenchyma due to microvascular disruption.
Instead, the study proposes that increased interactions between RBC and brain capillary endothelium may represent an alternative source of CMH development. This alternative viewpoint holds potential clinical relevance, particularly for conditions associated with heightened RBC stress, such as sickle cell disease, chronic kidney disease, and possibly aged RBC.Â
This study sheds light on the intricate dynamics of RBC–brain capillary interactions under oxidative stress, providing valuable insights into CMH development. The findings not only contribute to our understanding of CMH in various health conditions but also offer potential avenues for targeted interventions and treatments, particularly in the context of aging populations and diseases associated with increased RBC stress. Â
Journal Reference Â
Hai Zhang et al, Erythrocyte–brain endothelial interactions induce microglial responses and cerebral micro haemorrhages in vivo, Journal of Neuroinflammation (2023). DOI: 10.1186/s12974-023-02932-5Â
