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 involved in cGMP- and cAMP-mediated inhibition of agonist-induced platelet aggregation, but is dispensable for smooth muscle function
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DOI：
10.1093/emboj/18.1.37
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发表时间：
1999-01-04
期刊：
影响因子：
11.4
通讯作者：
Fässler, R
中科院分区：
文献类型：
--
作者：
Aszódi, A;Pfeifer, A;Fässler, R
血管扩张剂刺激的磷酸蛋白(VASP)与肌动蛋白细丝和局部粘连相关，形成细胞骨架和细胞外基质之间的界面。在包括血小板和平滑肌细胞在内的多种细胞中，VASP都被cAMP和cGMP依赖的蛋白激酶所磷酸化，因为cAMP和cGMP信号级联都可以松弛平滑肌并抑制血小板的激活，推测VASP通过调节肌动蛋白细丝动力学和整合素的激活来介导这些作用。为了研究Vasp在这些过程中的生理相关性，我们在小鼠中灭活了Vasp基因。成年Vasp缺陷小鼠有正常的激动剂诱导的收缩和正常的cAMP和cGMP依赖的肠和血管平滑肌松弛，而cAMP和cGMP介导的抑制血小板聚集的作用在没有Vasp的情况下显著减少，其他依赖于cAMP和cGMP的血小板效应，如抑制激动剂诱导的细胞内钙浓度和颗粒分泌，不依赖于Vasp的存在。核苷酸依赖的机制在血小板激活过程中起作用：Vasp依赖的机制抑制钙动员和颗粒释放，Vasp依赖的机制抑制血小板聚集，这可能涉及整合素功能的调节。
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.