Enhancement of vascular progenitor potential by protein kinase A through dual induction of Flk-1 and Neuropilin-1
Enhancement of vascular progenitor potential by protein kinase A through dual induction of Flk-1 and Neuropilin-1
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DOI：
10.1182/blood-2008-12-195750
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发表时间：
2009-10-22
期刊：
影响因子：
20.3
通讯作者：
Yamashita, Jun K.
中科院分区：
文献类型：
--
作者：
Yamamizu, Kohei;Kawasaki, Kyoko;Yamashita, Jun K.
血管内皮生长因子(VEGF)信号的微调在内皮细胞(EC)分化和血管发育中起着至关重要的作用。然而，调节血管内皮生长因子信号敏感性的系统仍然不清楚。在此之前，我们建立了以Flk1(血管内皮生长因子受体-2)(+)细胞为共同祖细胞的早期血管发育胚胎干细胞培养体系，并证明了环磷酸腺苷(CAMP)促进了血管内皮生长因子诱导的EC分化。在这里，我们发现蛋白激酶A(PKA)调节Flk1(+)血管前体细胞对血管内皮生长因子信号的敏感性，以实现有效的EC分化。阻断PKA干扰内皮细胞分化和血管形成。构建活性形式的PKA(CA-PKA)过表达可有效地诱导EC分化和血管形成。Flk1和Neuropilin-1(Nrp1)是VEGF165的选择性和敏感性受体，仅在表达CA-PKA的祖细胞中表达增加，使其对VEGF(165)的敏感性增加10倍以上。PKA活化可诱导血管祖细胞形成血管内皮生长因子(165)、Flk1和Nrp1蛋白复合体。这些数据表明，PKA通过Flk1和Nrp1的双重诱导，调节血管前体细胞的分化潜能，使其具有内皮活性。这种调节“祖细胞敏感性”的新机制将为血管发育和再生提供新的理解。(血。2009；114：3707-3716)
Fine tuning of vascular endothelial growth factor (VEGF) signaling is critical in endothelial cell (EC) differentiation and vascular development. Nevertheless, the system for regulating the sensitivity of VEGF signaling has remained unclear. Previously, we established an embryonic stem cell culture reproducing early vascular development using Flk1 (VEGF receptor-2) (+) cells as common progenitors, and demonstrated that cyclic adenosine monophosphate (cAMP) enhanced VEGF-induced EC differentiation. Here we show that protein kinase A (PKA) regulates sensitivity of Flk1(+) vascular progenitors to VEGF signaling for efficient EC differentiation. Blockade of PKA perturbed EC differentiation and vascular formation in vitro and ex vivo. Overexpression of constitutive active form of PKA (CA-PKA) potently induced EC differentiation and vascular formation. Expression of Flk1 and Neuropilin-1 (NRP1), which form a selective and sensitive receptor for VEGF165, was increased only in CA-PKA-expressing progenitors, enhancing the sensitivity of the progenitors to VEGF(165) by more than 10 times. PKA activation induced the formation of a VEGF(165), Flk1, and NRP1 protein complex in vascular progenitors. These data indicate that PKA regulates differentiation potential of vascular progenitors to be endothelial competent via the dual induction of Flk1 and NRP1. This new-mode mechanism regulating "progenitor sensitivity" would provide a novel understanding in vascular development and regeneration. (Blood. 2009; 114: 3707-3716)