title: Enhanced in vivo platelet adhesion in vasodilator-stimulated phosphoprotein (VASP)-deficient mice.
abstract: Platelet adhesion and activation at the vascular wall are the initial steps leading to arterial thrombosis and vascular occlusion. Prostacyclin and nitric oxide inhibit platelet adhesion, acting via cyclic adenosine monophosphate (cAMP)- and cyclic guanosine monophosphate (cGMP)-dependent protein kinases. A major downstream target for both cAMP- and cGMP-dependent protein kinases is the vasodilator-stimulated phosphoprotein (VASP). To test the significance of VASP for the regulation of platelet adhesion in vivo, we studied platelet-vessel wall interactions using VASP-deficient (VASP-/-) mice. Under physiologic conditions, platelet adhesion to endothelial cells was significantly enhanced in VASP null mutants when compared with wild-type mice (P <.05). Platelet recruitment in VASP null mice involved P-selectin and the fibrinogen receptor glycoprotein IIb-IIIa (GPIIb-IIIa). Under pathophysiologic conditions, the loss of VASP increased platelet adhesion to the postischemic intestinal microvasculature, to the atherosclerotic endothelium of ApoE-deficient mice, and to the subendothelial matrix following endothelial denudation (P <.05 vs wild type). Importantly, platelet adhesion in VASP null mutants was unresponsive to nitric oxide. These data show for the first time in vivo that VASP is involved in down-regulation of platelet adhesion to the vascular wall under both physiologic and pathophysiologic conditions.
authors.affiliation: Deutsches Herzzentrum und 1, Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, München, Germany. massberg@dhm.mhn.de
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.forename: Sabine
authors.initials: S
authors.lastname: Grüner
authors.forename: Ildiko
authors.initials: I
authors.lastname: Konrad
authors.forename: Maisa I
authors.initials: MI
authors.lastname: Garcia Arguinzonis
authors.forename: Martin
authors.initials: M
authors.lastname: Eigenthaler
authors.forename: Kathrin
authors.initials: K
authors.lastname: Hemler
authors.forename: Julia
authors.initials: J
authors.lastname: Kersting
authors.forename: Christian
authors.initials: C
authors.lastname: Schulz
authors.forename: Iris
authors.initials: I
authors.lastname: Muller
authors.forename: Felicitas
authors.initials: F
authors.lastname: Besta
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Ulrich
authors.initials: U
authors.lastname: Heinzmann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
mesh_terms: D000818:Animals; D016893:Carotid Stenosis / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000502:physiology*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D020030:Nitric Oxide Donors; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein