title: Matrix stiffness exerts biphasic control over monocyte-endothelial adhesion via Rho-mediated ICAM-1 clustering.
abstract: Leukocyte-endothelial adhesion is a critical early step in chronic vascular inflammation associated with diabetes, emphysema, and aging. Importantly, these conditions are also marked by abnormal subendothelial matrix crosslinking (stiffness). Yet, whether and how abnormal matrix stiffness contributes to leukocyte-endothelial adhesion remains poorly understood. Using a co-culture of human monocytic cells and human microvascular endothelial cells (ECs) grown on matrices of tunable stiffness, we demonstrate that matrix stiffness exerts biphasic control over monocyte-EC adhesion, with both matrix softening and stiffening eliciting a two-fold increase in this adhesive interaction. This preferential endothelial adhesivity on softer and stiffer matrices was consistent with a significant increase in α-actinin-4-associated endothelial ICAM-1 clustering, a key determinant of monocyte-EC adhesion. Further, the enhanced ICAM-1 clustering on soft and stiff matrices correlated strongly with an increase in Rho activity and ROCK2 expression. Importantly, inhibition of Rho/ROCK activity blocked the effects of abnormal matrix stiffness on ICAM-1 clustering and monocyte-EC adhesion. Thus, these findings implicate matrix stiffness-dependent ICAM-1 clustering as an important regulator of vascular inflammation and provide the rationale for closely examining mechanotransduction pathways as new molecular targets for anti-inflammatory therapy.
authors.affiliation: Department of Bioengineering, University of California Riverside, 900 University Avenue, MSE 207, Riverside, CA 92521, USA. kghosh@engr.ucr.edu.
authors.forename: Harry A
authors.initials: HA
authors.lastname: Scott
authors.forename: Boi
authors.initials: B
authors.lastname: Quach
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.forename: Soroush
authors.initials: S
authors.lastname: Ardekani
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Cabrera
authors.forename: Randall
authors.initials: R
authors.lastname: Wilson
authors.forename: Ilhem
authors.initials: I
authors.lastname: Messaoudi-Powers
authors.forename: Kaustabh
authors.initials: K
authors.lastname: Ghosh
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D000185:Actinin / Q000378:metabolism; D002448:Cell Adhesion; D016000:Cluster Analysis; D018920:Coculture Techniques; D003599:Cytoskeleton / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology; D040542:Mechanotransduction, Cellular; D008833:Microcirculation; D009000:Monocytes / Q000166:cytology*; D011312:Pressure; D015398:Signal Transduction; D020298:U937 Cells; D054460:rho-Associated Kinases / Q000378:metabolism*; D000099166:Polyacrylamides
chemical_list: D000180:Acrylic Resins; D000185:Actinin; D018799:Intercellular Adhesion Molecule-1; D054460:rho-Associated Kinases; D000099166:Polyacrylamides; C573420:ICAM1 protein, human