Differential Vulnerability and Response to Injury among Brain Cell Types Comprising the Neurovascular Unit

The neurovascular unit includes multiple different cell types, including neurons, astrocytes, endothelial cells and pericytes, which respond to insults on very different time or dose scales. We defined differential vulnerability among these cell types, using response to two different insults: oxygen-glucose deprivation and thrombin-mediated cytotoxicity. We found that neurons are most vulnerable, followed by endothelial cells, followed by astrocytes. After temporary focal cerebral ischemia in male rats, we found significantly more injured neurons, compared to astrocytes in the ischemic area, consistent with differential vulnerability in vivo. We sought to illustrate different and shared mechanisms across all cell types during response to insult. We found that gene expression profiles in response to oxygen-glucose deprivation differed among the cell types, with a paucity of gene responses shared by all types. All cell types activated genes relating to autophagy, apoptosis, and necroptosis, but the specific genes differed. Astrocytes and endothelial cells also activated pathways connected to DNA repair and anti-apoptosis. Taken together, the data support the concept of differential vulnerability in the neurovascular unit and suggests that different elements of the unit will evolve from salvageable to irretrievable on different time scales while residing in the same brain region and receiving the same (ischemic) blood flow. Future work will focus on the mechanisms of these differences. These data suggest future stroke therapy development should target different elements of the NVU differently.Significance StatementFor decades, stroke treatments proven effective in pre-clinical models have failed in human clinical trials. Experimental, pre-clinical evaluation has focused mostly on protecting neurons, assuming that glia and vascular cells also would be protected. We now define and demonstrate differential vulnerability to insult as well as differential response to treatment among the various brain cell types comprising the neurovascular unit. Neurons, astrocytes, and endothelial cells show markedly different responses to ischemia. Ignoring differential vulnerability and treatment response may explain past clinical trial failures. Future studies should determine the mechanisms that underly differential vulnerability in the neurovascular unit.