Interdepartmental Program in Vascular Biology and Therapeutics, Department of Immunobiology, Yale University School of Medicine, 10 Amistad St., New Haven, CT 06520, USA.
Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):633-42. doi: 10.1161/ATVBAHA.111.243576. Epub 2012 Jan 5.
Vascular endothelial growth factor receptor(VEGFR)-3 is a critical regulator of developmental and adult vasculogenesis and lymphangiogenesis through its interactions with select members of the VEGF family. The goal of this study was to investigate how VEGFR-3 expression is regulated during inflammatory lymphangiogenesis.
In this study, we present for the first time evidence that VEGFR-3 can be negatively regulated by a mirtron, hsa-miR-1236 (miR-1236), which is expressed in primary human lymphatic endothelial cells. In human lymphatic endothelial cells, miR-1236 is upregulated in response to IL-1β, a negative regulator of VEGFR-3. miR-1236 binds the 3' untranslated region of Vegfr3, resulting in translational inhibition. Overexpression of miR-1236 significantly decreased expression of VEGFR-3, but not VEGFR-2, in human lymphatic endothelial cells. Compared to a control miR, overexpression of miR-1236 also led to decreased VEGFR-3 signaling. However, VEGFR-2-specific signaling was not affected. miR-1236 can attenuate human lymphatic endothelial cell migration and tube formation, as well as in vivo lymphangiogenesis.
Our data suggest that miR-1236 may function as a negative regulator of VEGFR-3 signaling during inflammatory lymphangiogenesis.
血管内皮生长因子受体(VEGFR)-3 通过与 VEGF 家族的特定成员相互作用，成为发育和成人血管生成和淋巴管生成的关键调节因子。本研究的目的是研究 VEGFR-3 在炎症性淋巴管生成过程中的表达是如何被调节的。
在这项研究中，我们首次提出证据表明，miR-1236（miR-1236）可以负调控 VEGFR-3，miR-1236 是在原代人淋巴管内皮细胞中表达的 mirtron。在人淋巴管内皮细胞中，miR-1236 在内毒素β（IL-1β）的刺激下上调，IL-1β 是 VEGFR-3 的负调控因子。miR-1236 结合 Vegfr3 的 3'非翻译区，导致翻译抑制。miR-1236 的过表达显著降低了人淋巴管内皮细胞中 VEGFR-3 的表达，但不降低 VEGFR-2 的表达。与对照 miR 相比，miR-1236 的过表达也导致 VEGFR-3 信号转导减少。然而，VEGFR-2 特异性信号转导不受影响。miR-1236 可减弱人淋巴管内皮细胞的迁移和管形成，以及体内淋巴管生成。
我们的数据表明，miR-1236 可能在炎症性淋巴管生成过程中作为 VEGFR-3 信号的负调节剂发挥作用。
