The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis
The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis
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DOI：
10.1038/ncomms1977
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发表时间：
2012-07-01
影响因子：
16.6
通讯作者：
Ahmed, Asif
中科院分区：
文献类型：
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作者：
Cudmore, Melissa J.;Hewett, Peter W.;Ahmed, Asif
VEGF-A活性受配体和受体可用性的严格调节。在此，我们研究了内皮细胞中VEGF受体-1（VEGFR-1; Flt-1）和VEGFR-2（KDR; Flk-1）（VEGFR（1-2））之间异二聚体的生理功能，该异二聚体具有与VEGFR（1-2）特异性结合的合成配体。二聚体配体包含一个VEGFR-2特异性单体（VEGF-E）和VEGFR-1特异性单体（PlGF-1）。在这里，我们表明，VEGFR（1-2）激活介导的VEGFR磷酸化，内皮细胞迁移，持续在体外管形成和血管舒张通过一氧化氮途径。VEGFR（1-2）活化不介导增殖或引起内皮组织因子产生，证实这些功能受VEGFR-2同源二聚体控制。我们进一步证实，VEGFR（1-2）的激活抑制VEGF-A诱导的前列环素释放、ERK 1/2 MAP激酶磷酸化和原代内皮细胞胞内钙的动员。这些发现表明，VEGFR-1亚基主要通过与VEGFR-2亚基形成异源二聚体受体来调节VEGF活性，并且这种异源二聚体调节内皮细胞稳态。
VEGF-A activity is tightly regulated by ligand and receptor availability. Here we investigate the physiological function of heterodimers between VEGF receptor-1 (VEGFR-1; Flt-1) and VEGFR-2 (KDR; Flk-1) (VEGFR(1-2)) in endothelial cells with a synthetic ligand that binds specifically to VEGFR(1-2). The dimeric ligand comprises one VEGFR-2-specific monomer (VEGF-E) and a VEGFR-1-specific monomer (PlGF-1). Here we show that VEGFR(1-2) activation mediates VEGFR phosphorylation, endothelial cell migration, sustained in vitro tube formation and vasorelaxation via the nitric oxide pathway. VEGFR(1-2) activation does not mediate proliferation or elicit endothelial tissue factor production, confirming that these functions are controlled by VEGFR-2 homodimers. We further demonstrate that activation of VEGFR(1-2) inhibits VEGF-A-induced prostacyclin release, phosphorylation of ERK1/2 MAP kinase and mobilization of intracellular calcium from primary endothelial cells. These findings indicate that VEGFR-1 subunits modulate VEGF activity predominantly by forming heterodimer receptors with VEGFR-2 subunits and such heterodimers regulate endothelial cell homeostasis.