High-Throughput Screening of Vascular Endothelium-Destructive or Protective Microenvironments: Cooperative Actions of Extracellular Matrix Composition, Stiffness, and Structure.
Pathological modification of the subendothelial extracellular matrix (ECM) has closely been associated with endothelial activation and subsequent cardiovascular disease progression. To understand regulatory mechanisms of these matrix modifications, the majority of previous efforts have focused on the modulation of either chemical composition or matrix stiffness on 2D smooth surfaces without simultaneously probing their cooperative effects on endothelium function on in vivo like 3D fibrous matrices. To this end, a high-throughput, combinatorial microarray platform on 2D and 3D hydrogel settings to resemble the compositions, stiffness, and structure of healthy and diseased subendothelial ECM has been established, and further their respective and combined effects on endothelial attachment, proliferation, inflammation, and junctional integrity have been investigated. For the first time, the results demonstrate that 3D fibrous structure resembling native ECM is a critical endothelium-protective microenvironmental factor by maintaining the stable, quiescent endothelium with strong resistance to proinflammatory stimuli. It is also revealed that matrix stiffening, in concert with chemical compositions resembling diseased ECM, particularly collagen III, could aggravate activation of nuclear factor kappa B, disruption of endothelium integrity, and susceptibility to proinflammatory stimuli. This study elucidates cooperative effects of various microenvironmental factors on endothelial activation and sheds light on new in vitro model for cardiovascular diseases.
Department of Mechanical Engineering, University of Colorado at Boulder, Boulder, CO, 80309, USA.
Yonghui
Y
Ding
Department of Mechanical Engineering, University of Colorado at Boulder, Boulder, CO, 80309, USA.|Cardiovascular Pulmonary Research and Developmental Lung Biology Laboratories, University of Colorado Denver, Aurora, CO, 80045, USA.
Michael
M
Floren
Department of Mechanical Engineering, University of Colorado at Boulder, Boulder, CO, 80309, USA.
Wei
W
Tan
D000818:Animals; D002417:Cattle; D060833:Cellular Microenvironment; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D020100:Hydrogels / Q000737:chemistry*; D008955:Models, Cardiovascular; D014652:Vascular Diseases / Q000378:metabolism* / Q000473:pathology; D059289:Vascular Stiffness
D020100:Hydrogels
3D fibrous structure; endothelium; extracellular matrix array; stiffness