Microvascular endothelial cells display organ-specific responses to extracellular matrix stiffness

Haidari, Rana, Fowler, Wesley J., Robinson, Stephen D., Johnson, Robert T. and Warren, Derek T. (2025) Microvascular endothelial cells display organ-specific responses to extracellular matrix stiffness. Current Research in Physiology, 8. ISSN 2665-9441

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Abstract

The extracellular matrix was originally thought of as simply a cellular scaffold but is now considered a key regulator of cell function and phenotype from which cells can derive biochemical and mechanical stimuli. Age-associated changes in matrix composition drive increases in matrix stiffness. Enhanced matrix stiffness promotes the progression of numerous diseases including cardiovascular disease, musculoskeletal disease, fibrosis, and cancer. Macrovascular endothelial cells undergo endothelial dysfunction in response to enhanced matrix stiffness. However, endothelial cells are highly heterogeneous, adopting structural and gene expression profiles specific to their organ of origin. Endothelial cells isolated from different vessels (i.e. arteries, veins or capillaries) respond differently to changes in substrate stiffness. It is unknown whether microvascular endothelial cells isolated from different organs also display organ-specific responses to substrate stiffness. In this study, we compare the response of microvascular endothelial cells isolated from both the mouse lung and mammary gland to a range of physiologically relevant substrate stiffnesses. We find that endothelial origin influences microvascular endothelial cell response to substrate stiffness in terms of both proliferation and migration speed. In lung-derived endothelial cells, proliferation is bimodal, where both physiologically soft and stiff substrates drive enhanced proliferation. Conversely, in mammary gland-derived endothelial cells, proliferation increases as substrate stiffness increases. Substrate stiffness also promotes enhanced endothelial migration. Enhanced stiffness drove greater increases in migration speed in mammary gland-derived than lung-derived endothelial cells. However, stiffness-induced changes in microvascular endothelial cell morphology were consistent between both cell lines, with substrate stiffness driving an increase in endothelial volume. Our research demonstrates the importance of considering endothelial origin in experimental design, especially when investigating how age-associated changes in matrix stiffness drive endothelial dysfunction and disease progression.

Item Type:	Article
Uncontrolled Keywords:	sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Science Faculty of Science > School of Biological Sciences Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging Faculty of Science > Research Groups > Cells and Tissues Faculty of Science > Research Groups > Molecular and Tissue Pharmacology
Depositing User:	LivePure Connector
Date Deposited:	04 Feb 2025 16:16
Last Modified:	10 Feb 2025 01:18
URI:	https://ueaeprints.uea.ac.uk/id/eprint/98372
DOI:	10.1016/j.crphys.2025.100140

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