The vasodilator-stimulated phosphoprotein (VASP) is involved in cGMP- and cAMP-mediated inhibition of agonist-induced platelet aggregation, but is dispensable for smooth muscle function.
The vasodilator-stimulated phosphoprotein (VASP) is associated with actin filaments and focal adhesions, which form the interface between the cytoskeleton and the extracellular matrix. VASP is phosphorylated by both the cAMP- and cGMP-dependent protein kinases in a variety of cells, including platelets and smooth muscle cells. Since both the cAMP and cGMP signalling cascades relax smooth muscle and inhibit platelet activation, it was speculated that VASP mediates these effects by modulating actin filament dynamics and integrin activation. To study the physiological relevance of VASP in these processes, we inactivated the VASP gene in mice. Adult VASP-deficient mice had normal agonist-induced contraction, and normal cAMP- and cGMP-dependent relaxation of intestinal and vascular smooth muscle. In contrast, cAMP- and cGMP-mediated inhibition of platelet aggregation was significantly reduced in the absence of VASP. Other cAMP- and cGMP-dependent effects in platelets, such as inhibition of agonist-induced increases in cytosolic calcium concentrations and granule secretion, were not dependent on the presence of VASP. Our data show that two different cyclic, nucleotide-dependent mechanisms are operating during platelet activation: a VASP-independent mechanism for inhibition of calcium mobilization and granule release and a VASP-dependent mechanism for inhibition of platelet aggregation which may involve regulation of integrin function.
Aszódi
A
A
Department of Experimental Pathology, Lund University, Lund, Sweden.
Pfeifer
A
A
Ahmad
M
M
Glauner
M
M
Zhou
X H
XH
Ny
L
L
Andersson
K E
KE
Kehrel
B
B
Offermanns
S
S
Fässler
R
R
D000818:Animals; D001483:Base Sequence; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000097:blood; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D000242:Cyclic AMP / Q000097:blood / Q000494:pharmacology; D006152:Cyclic GMP / Q000097:blood / Q000494:pharmacology; D003598:Cytoskeletal Proteins; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D009126:Muscle Relaxation / Q000502:physiology; D009130:Muscle, Smooth / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology; D012701:Serotonin / Q000097:blood; D000098662:Vasodilator-Stimulated Phosphoprotein
D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D017931:DNA Primers; C102176:Enah protein, mouse; C102177:Evl protein, mouse; D008840:Microfilament Proteins; D010750:Phosphoproteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011506:Proteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D012701:Serotonin; D000242:Cyclic AMP; D006152:Cyclic GMP; D002118:Calcium