Congratulations to Alexis Yates in the Lippmann lab! Dr. Yates article “Substrate stiffness and shear stress collectively regulate the inflammatory phenotype in cultured human brain microvascular endothelial cells” has been selected as a VINSE spotlight publication.
Lexi Yates received her Ph.D. in Interdisciplinary Materials Science from Vanderbilt University in 2025 under the supervision of Professors Ethan Lippmann & Angela Jefferson. Dr. Yates is currently a Postdoctoral Research in the Department of Neurology at Northwestern University under the supervision of Dr. Farzaneh Sorond MD/Ph.D.
Brain microvascular endothelial cells (BMECs) are highly specialized endothelial cells that make up the internal lining of small blood vessels in the brain and are an integral part of the blood-brain barrier (BBB). By tightly controlling the exchange of cells and solutes, the BBB serves an important role in regulating inflammation and transport between the brain and the rest of the body. In addition to their role in forming the BBB, BMECs, like all endothelial cells, are equipped with mechanosensitive protein complexes which serve an important role in blood flow regulation. BMECs experience various mechanical forces in the form of blood flow-mediated shear stress, circumferential strain during vasodilation, and basement membrane stiffness. The intersectional contributions of these factors towards BBB impairment and neurovascular dysfunction have not been extensively studied in a cell culture model and are difficult to isolate in vivo. In this study, we developed perfused in vitro models to examine how primary BMECs respond to changes in the stiffness of a hydrogel substrate, in the presence and absence of fluid shear stress, mimicking two of the mechanical forces that BMECs experience in vivo. Our study demonstrates that subculturing BMECs on intermediate stiffness hydrogels promote a robust inflammatory response, which is slightly reduced when low shear stress is introduced to the system. These data support the growing appreciation for the role of vascular stiffening in contributing to endothelial dysfunction and inflammation in the brain.
Authors: Alexis K. Yates, Heather Murray, Andrew Kjar, Daniel Chavarria, Haley Masters, Hyosung Kim, Alexander P. Ligocki, Angela L. Jefferson and Ethan S. Lippmann
Abstract: Brain endothelial cells experience mechanical forces in the form of blood flow-mediated shear stress and underlying matrix stiffness, but intersectional contributions of these factors towards blood–brain barrier (BBB) impairment and neurovascular dysfunction have not been extensively studied. Here, we developed in vitro models to examine the sensitivity of primary human brain microvascular endothelial cells (BMECs) to substrate stiffness, with or without exposure to fluid shear stress. Using a combination of molecular profiling techniques, we show that BMECs exhibit an inflammatory signature at both the mRNA and protein level when cultured on gelatin substrates of intermediate stiffness (~ 30 kPa) versus soft substrates (~ 6 kPa). Exposure to modest fluid shear stress (1.7 dyne/cm2) partially attenuated this signature, including reductions in levels of soluble chemoattractants and surface ICAM-1. Overall, our results indicate that increased substrate stiffness promotes an inflammatory phenotype in BMECs that is dampened in the presence of fluid shear stress.