title: Multiple integrin-ligand interactions synergize in shear-resistant platelet adhesion at sites of arterial injury in vivo.
abstract: Damage to the integrity of the vessel wall results in exposure of the subendothelial extracellular matrix (ECM), which triggers integrin-dependent adhesion and aggregation of platelets. The role of platelet beta1 integrins in these processes remains mostly undefined. Here, we demonstrate by intravital fluorescence microscopy that platelet adhesion and thrombus growth on the exposed ECM of the injured carotid artery is not significantly altered in alpha2-null mice and even in mice with a Cre/loxP-mediated loss of all beta1 integrins on their platelets. In contrast, inhibition of alphaIIbbeta3 integrin on platelets in wild-type mice blocked aggregate formation and reduced platelet adhesion by 60.0%. Strikingly, alphaIIbbeta3 inhibition had a comparable effect in alpha2-null mice, demonstrating that other receptors mediate shear-resistant adhesion in the absence of functional alpha2beta1 and alphaIIbbeta3. These were identified to be alpha5beta1 and/or alpha6beta1 as alphaIIbbeta3 inhibition abrogated platelet adhesion in beta1-null mice. We conclude that shear-resistant platelet adhesion on the injured vessel wall in vivo is a highly integrated process involving multiple integrin-ligand interactions, none of which by itself is essential.
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Versbacher Str 9, 97078 Würzburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Grüner
authors.forename: Miroslava
authors.initials: M
authors.lastname: Prostredna
authors.forename: Valerie
authors.initials: V
authors.lastname: Schulte
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.forename: Beate
authors.initials: B
authors.lastname: Eckes
authors.forename: Cord
authors.initials: C
authors.lastname: Brakebusch
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000473:pathology*; D004730:Endothelium, Vascular; D005109:Extracellular Matrix; D018056:Hemorheology; D038982:Integrin alpha2beta1 / Q000378:metabolism / Q000502:physiology; D039081:Integrin alpha5beta1 / Q000378:metabolism / Q000502:physiology; D039121:Integrin alpha6beta1 / Q000378:metabolism / Q000502:physiology; D016023:Integrins / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D018715:Microscopy, Video; D010973:Platelet Adhesiveness / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D013927:Thrombosis / Q000209:etiology* / Q000473:pathology
chemical_list: D038982:Integrin alpha2beta1; D039081:Integrin alpha5beta1; D039121:Integrin alpha6beta1; D016023:Integrins; D008024:Ligands; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI