The impact of endothelial cell death in the brain and its role after stroke: A systematic review

Abstract

The supply of oxygen and nutrients to the brain is vital for its function and requires a complex vascular network that, when disturbed, results in profound neurological dysfunction. As part of the pathology in stroke, endothelial cells die. As endothelial cell death affects the surrounding cellular environment and is a potential target for the treatment and prevention of neurological disorders, we have systematically reviewed important aspects of endothelial cell death with a particular focus on stroke. After screening 2876 publications published between January 1, 2010 and August 7, 2019, we identified 154 records to be included. We found that endothelial cell death occurs rapidly as well as later after the onset of stroke conditions. Among the different cell death mechanisms, apoptosis was the most widely investigated (92 records), followed by autophagy (20 records), while other, more recently defined mechanisms received less attention, such as lysosome-dependent cell death (2 records) and necroptosis (2 records). We also discuss the differential vulnerability of brain cells to injury after stroke and the role of endothelial cell death in the no-reflow phenomenon with a special focus on the microvasculature. Further investigation of the different cell death mechanisms using novel tools and biomarkers will greatly enhance our understanding of endothelial cell death. For this task, at least two markers/criteria are desirable to determine cell death subroutines according to the recommendations of the Nomenclature Committee on Cell Death.

Histological correlates of postmortem ultra-high-resolution single-section MRI in cortical cerebral microinfarcts

“…Development of string vessels can be also mediated by a loss of factors that promote endothelial cell survival and angiogenesis such as vascular endothelial growth factor (VEGF) [3,10,40]. In our cases, Coll4-positive string vessels at microinfarcts and their periphery lacked UEA-l expression indicating endothelial recession, which is associated with cessation of blood perfusion in the vessels affected [10,22,55]. Thus, the presence of string vessels pointed to disturbances in the microcirculation in and around cortical cerebral microinfarcts, which may explain the comparatively strong MRI signals obtained from relatively small cortical microinfarcts in vivo [27,28,32].…”

The endothelium, a key actor in organ development and hPSC-derived organoid vascularization

“…CECs are surrounded by a basement membrane, astrocyte cytoplasmic extensions and pericytes and have an estimated total surface coverage of 99%. Dysfunctional ECs appeared to contribute to the development and maintenance of pathological phenotypes such as cerebral ischemia [56] or neurological disorders [57,58].…”

Modeling blood–brain barrier pathology in cerebrovascular disease in vitro: current and future paradigms

“…A third mechanism of BBB injury modeled in vitro is cytotoxicity/excitotoxicity. Endothelial cell death (apoptosis, lysosome-dependent necroptosis) does occur during cerebral ischemia and cytotoxic mechanisms and potential therapies can be studied in vitro with OGD [174]. Similarly, the generation of reactive oxygen species and related cell injury that occurs during reperfusion is mimicked during the 'reperfusion' phase after OGD.…”