Role of PIGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1
Role of PIGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1
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DOI：
10.1038/nm884
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发表时间：
2003-07-01
期刊：
影响因子：
82.9
通讯作者：
Carmeliet, P
中科院分区：
文献类型：
--
作者：
Autiero, M;Waltenberger, J;Carmeliet, P
治疗性血管生成可能需要施用相互补充的因子。血管内皮生长因子 (VEGF) 激活受体酪氨酸激酶 (RTK) Flk1 至关重要，但其他因子与 VEGF 和 Flk1 的分子相互作用的研究程度有限。在这里，我们报道胎盘生长因子（PGF，也称为 PIGF）调节 VEGF RTK Flt1 和 Flk1 之间的分子间和分子内串扰。 PGF 激活 Flt1 导致 Flk1 分子间转磷酸化，从而通过 Flk1 放大 VEGF 驱动的血管生成。尽管 VEGF 和 PGF 均结合 Flt1，但 PGF 独特地刺激特定 Flt1 酪氨酸残基的磷酸化和不同下游靶基因的表达。此外，VEGF/PGF 异二聚体通过形成 Flk1/Flt1 异二聚体激活分子内 VEGF 受体串扰。分子间和分子内 VEGF 受体串扰可能具有治疗意义，因为使用 VEGF/PGF 异二聚体或 VEGF 加 PGF 联合治疗可增加仅用 VEGF 治疗无效的小鼠模型中的缺血性心肌血管生成。
Therapeutic angiogenesis is likely to require the administration of factors that complement each other. Activation of the receptor tyrosine kinase (RTK) Flk1 by vascular endothelial growth factor (VEGF) is crucial, but molecular interactions of other factors with VEGF and Flk1 have been studied to a limited extent. Here we report that placental growth factor (PGF, also known as PIGF) regulates inter- and intramolecular cross talk between the VEGF RTKs Flt1 and Flk1. Activation of Flt1 by PGF resulted in intermolecular transphosphorylation of Flk1, thereby amplifying VEGF-driven angiogenesis through Flk1. Even though VEGF and PGF both bind Flt1, PGF uniquely stimulated the phosphorylation of specific Flt1 tyrosine residues and the expression of distinct downstream target genes. Furthermore, the VEGF/PGF heterodimer activated intramolecular VEGF receptor cross talk through formation of Flk1/Flt1 heterodimers. The inter- and intramolecular VEGF receptor cross talk is likely to have therapeutic implications, as treatment with VEGF/PGF heterodimer or a combination of VEGF plus PGF increased ischemic myocardial angiogenesis in a mouse model that was refractory to VEGF alone.