Transcriptional Responses of In Vitro Blood-Brain Barrier Models to Shear Stress

Endothelial cells throughout the body sense blood flow, eliciting transcriptional and phenotypic responses. The brain endothelium, known as the blood-brain barrier (BBB), possesses unique barrier and transport properties, which are in part regulated by blood flow. We utilized RNA sequencing to analyze the transcriptome of primary cultured rat brain microvascular endothelial cells (BMECs), as well as three human induced pluripotent stem cell-derived models. We compared the transcriptional responses of these cells to either low (0.5 dyne/cm²) or high (12 dyne/cm²) shear stresses, and subsequent analyses identified genes and pathways that were influenced by shear including key BBB-associated genes (SLC2A1, LSR, PLVAP) and canonical endothelial shear-stress-response transcription factors (KLF2, KLF4). In addition, our analysis suggests that shear alone is insufficient to rescue the de-differentiation caused by in vitro primary BMEC culture. Overall, these datasets and analyses provide new insights into the influence of shear on BBB models that will aid in model selection and guide further model development.