Megakaryocyte hyperplasia and enhanced agonist-induced platelet activation in vasodilator-stimulated phosphoprotein knockout mice.
Vasodilator-stimulated phosphoprotein (VASP), a substrate of cAMP- and cGMP-dependent protein kinases, is associated with focal adhesions, cell-cell contacts, microfilaments, and highly dynamic membrane regions. VASP, which is expressed in most cell types and in particularly high levels in human platelets, binds to profilin, zyxin, vinculin, F-actin, and the Listeria monocytogenes surface protein ActA. VASP is a member of the enabled (Ena)/VASP protein family and is thought to be involved in actin filament formation and integrin alphaIIbbeta3 inhibition in human platelets. To gain further insight into the in vivo function of this protein, VASP-deficient mice were generated by homologous recombination. VASP-/- mice demonstrated hyperplasia of megakaryocytes in bone marrow and spleen but exhibited no other macroscopic or microscopic abnormalities. Activation of platelets with thrombin induced a more than 2-fold higher surface expression of P-selectin and fibrinogen binding in VASP-deficient platelets in comparison to wild type. These data support the concept that VASP is a negative modulator of platelet and integrin alphaIIbbeta3 activation. Although the limited phenotypic differences between wild-type and VASP-/- mice suggested functional compensation of VASP by members of the Ena/VASP family, alterations in the expression levels of mammalian enabled (Mena) and Ena-VASP-like (Evl) protein were not detected. VASP-deficient mice may provide an interesting model system for diseases in which enhanced platelet activation plays a major role.
Institut für Klinische Biochemie und Pathobiochemie und, Josef-Schneider Strasse 2, 97080 Würzburg, Germany.
W
W
Hauser
K P
KP
Knobeloch
M
M
Eigenthaler
S
S
Gambaryan
V
V
Krenn
J
J
Geiger
M
M
Glazova
E
E
Rohde
I
I
Horak
U
U
Walter
M
M
Zimmer
D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000502:physiology*; D017931:DNA Primers; D018076:DNA, Complementary; D005260:Female; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008533:Megakaryocytes / Q000473:pathology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D009928:Organ Specificity; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology*; D015539:Platelet Activation / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D015183:Restriction Mapping; D000098662:Vasodilator-Stimulated Phosphoprotein
D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D018076:DNA, Complementary; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein