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首页> 外文期刊>American Journal of Physiology >VASP is involved in cAMP-mediated Rac 1 activation in microvascular endothelial cells.
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VASP is involved in cAMP-mediated Rac 1 activation in microvascular endothelial cells.

机译：VASP参与微血管内皮细胞中cAMP介导的Rac 1激活。

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摘要

Accumulating evidence points to a significant role of vasodilator-stimulated phosphoprotein (VASP) in the maintenance of endothelial barrier functions. We have recently shown that impaired barrier functions in VASP-deficient microvascular myocardial endothelial cells (MyEnd VASP(-/-)) correlated with decreased Rac 1 activity. To further test the hypothesis that VASP is involved in regulation of Rac 1 activity, we studied cAMP-dependent Rac 1 activation. Both inhibition of Rac 1 activation by NSC-23766 and inhibition of PKA by PKI completely blunted the efficacy of forskolin/rolipram (F/R)-mediated cAMP increase to stabilize barrier functions as revealed by measurements of transendothelial resistance (TER). Because these results indicate that PKA/Rac 1 activation is important for barrier stabilization, we tested this signaling pathway in VASP(-/-) cells. We found that F/R and isoproterenol reduced permeability measured as FITC-dextran flux across VASP(-/-) monolayers, but not below baseline levels of wild-type cells (WT). Moreover, cAMP-mediated Rac 1 activation was reduced to approximately 50% of WT levels, and both PKA inhibition by PKI and PKA anchoring via A kinase anchoring peptides (AKAPs) by HT31 almost completely abolished Rac 1 activation in VASP(-/-) and WT endothelium. Accordingly, HT31 significantly reduced F/R-mediated TER increase in WT cells and completely blocked the protective effect of cAMP on endothelial barrier properties. Together, our data underline the significant role of cAMP-mediated Rac 1 activation for endothelial barrier stabilization and demonstrate that both AKAP-mediated PKA anchoring and VASP are required for this process.
机译：越来越多的证据表明，血管舒张剂刺激的磷蛋白（VASP）在维持内皮屏障功能中起着重要作用。我们最近发现，VASP缺乏的微血管心肌内皮细胞（MyEnd VASP（-/-））中的屏障功能受损与Rac 1活性降低相关。为了进一步检验VASP参与调节Rac 1活性的假设，我们研究了cAMP依赖性Rac 1激活。 NSC-23766对Rac 1激活的抑制和PKI对PKA的抑制都完全削弱了佛司可林/咯利普兰（F / R）介导的cAMP增加以稳定屏障功能的功效，如通过跨内皮电阻（TER）的测量所揭示的。因为这些结果表明PKA / Rac 1激活对于屏障稳定很重要，所以我们在VASP（-/-）细胞中测试了该信号通路。我们发现F / R和异丙肾上腺素降低了通透VASP（-/-）单层的FITC-葡聚糖通量，但未低于野生型细胞（WT）的基线水平。此外，cAMP介导的Rac 1激活降低到WT水平的约50％，并且PKI的PKA抑制和HT31通过A激酶锚定肽（AKAPs）锚定的PKA几乎完全消除了VASP（-/-）中的Rac 1激活。和WT内皮。因此，HT31显着降低了WT细胞中F / R介导的TER增加，并完全阻断了cAMP对内皮屏障特性的保护作用。总之，我们的数据强调了cAMP介导的Rac 1激活对于内皮屏障稳定的重要作用，并证明了该过程需要AKAP介导的PKA锚定和VASP。

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