Enhanced in vivo platelet adhesion in vasodilator-stimulated phosphoprotein (VASP)-deficient mice.
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.
Massberg
Steffen
S
Deutsches Herzzentrum und 1, Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, München, Germany. massberg@dhm.mhn.de
Grüner
Sabine
S
Konrad
Ildiko
I
Garcia Arguinzonis
Maisa I
MI
Eigenthaler
Martin
M
Hemler
Kathrin
K
Kersting
Julia
J
Schulz
Christian
C
Muller
Iris
I
Besta
Felicitas
F
Nieswandt
Bernhard
B
Heinzmann
Ulrich
U
Walter
Ulrich
U
Gawaz
Meinrad
M
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
D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D020030:Nitric Oxide Donors; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein