title: Control of integrin alphaIIb beta3 outside-in signaling and platelet adhesion by sensing the physical properties of fibrin(ogen) substrates.
abstract: The physical properties of substrates are known to control cell adhesion via integrin-mediated signaling. Fibrin and fibrinogen, the principal components of hemostatic and pathological thrombi, may represent biologically relevant substrates whose variable physical properties control adhesion of leukocytes and platelets. In our previous work, we have shown that binding of fibrinogen to the surface of fibrin clot prevents cell adhesion by creating an antiadhesive fibrinogen layer. Furthermore, fibrinogen immobilized on various surfaces at high density supports weak cell adhesion whereas at low density it is highly adhesive. To explore the mechanism underlying differential cell adhesion, we examined the structural and physical properties of surfaces prepared by deposition of various concentrations of fibrinogen using atomic force microscopy and force spectroscopy. Fibrinogen deposition at high density resulted in an aggregated multilayered material characterized by low adhesion forces. In contrast, immobilization of fibrinogen at low density produced a single layer in which molecules were directly attached to the solid surface, resulting in higher adhesion forces. Consistent with their distinct physical properties, low- but not high-density fibrinogen induced strong alpha(IIb)beta(3)-mediated outside-in signaling in platelets, resulting in their spreading. Moreover, while intact fibrin gels induced strong signaling in platelets, deposition of fibrinogen on the surface of fibrin resulted in diminished cell signaling. The data suggest that deposition of a multilayered fibrinogen matrix prevents stable cell adhesion by modifying the physical properties of surfaces, which results in reduced force generation and insufficient signaling. The mechanism whereby circulating fibrinogen alters adhesive properties of fibrin clots may have important implications for control of thrombus formation and thrombogenicity of biomaterials.
authors.affiliation: Center for Metabolic Biology, Arizona State University, Tempe, Arizona 85287, USA.
authors.forename: Nataly P
authors.initials: NP
authors.lastname: Podolnikova
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Yermolenko
authors.forename: Alexander
authors.initials: A
authors.lastname: Fuhrmann
authors.forename: Valeryi K
authors.initials: VK
authors.lastname: Lishko
authors.forename: Sergei
authors.initials: S
authors.lastname: Magonov
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bowen
authors.forename: Joerg
authors.initials: J
authors.lastname: Enderlein
authors.forename: Andriy V
authors.initials: AV
authors.lastname: Podolnikov
authors.forename: Robert
authors.initials: R
authors.lastname: Ros
authors.forename: Tatiana P
authors.initials: TP
authors.lastname: Ugarova
mesh_terms: D001665:Binding Sites; D001792:Blood Platelets / Q000378:metabolism / Q000648:ultrastructure; D002448:Cell Adhesion; D003593:Cytoplasm; D005337:Fibrin / Q000737:chemistry* / Q000378:metabolism; D005340:Fibrinogen / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D018625:Microscopy, Atomic Force; D008855:Microscopy, Electron, Scanning; D010973:Platelet Adhesiveness / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D015398:Signal Transduction; D013499:Surface Properties
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005337:Fibrin; D005340:Fibrinogen