PDF(Pubmed)
Abstract：
Lymphatic capillaries develop discontinuous cell-cell junctions that permit the absorption of large macromolecules, chylomicrons, and fluid from the interstitium. While excessive vascular endothelial growth factor 2 (VEGFR2) signaling can remodel and seal these junctions, whether and how VEGFR3 can alter lymphatic junctions remains incompletely understood. Here, we use lymphatic-specific Flt4 knockout mice to investigate VEGFR3 signaling in lymphatic junctions. We show that loss of Flt4 prevents specialized button junction formation in multiple tissues and impairs interstitial absorption. Knockdown of FLT4 in human lymphatic endothelial cells results in impaired NOTCH1 expression and activation, and overexpression of the NOTCH1 intracellular domain in Flt4 knockout vessels rescues the formation of button junctions and absorption of interstitial molecules. Together, our data reveal a requirement for VEGFR3 and NOTCH1 signaling in the development of button junctions during postnatal development and may hold clinical relevance to lymphatic diseases with impaired VEGFR3 signaling.
摘要：
淋巴毛细血管形成不连续的细胞-细胞连接，允许吸收大分子，乳糜微粒,和间质的液体。虽然过度的血管内皮生长因子2（VEGFR2）信号可以重塑和密封这些连接，VEGFR3是否以及如何改变淋巴连接仍未完全了解。这里,我们使用淋巴特异性Flt4敲除小鼠来研究淋巴连接中的VEGFR3信号传导。我们表明，Flt4的丢失可防止多种组织中形成专门的纽扣连接，并损害间质吸收。人淋巴管内皮细胞中FLT4的敲除导致NOTCH1表达和活化受损,Flt4敲除血管中NOTCH1细胞内结构域的过表达挽救了按钮连接的形成和间质分子的吸收。一起,我们的数据显示,在出生后发育过程中,纽扣连接的发育需要VEGFR3和NOTCH1信号传导,并且可能与VEGFR3信号传导受损的淋巴疾病具有临床相关性.
