Antila Salli, Karaman Sinem, Nurmi Harri, Airavaara Mikko, Voutilainen Merja H, Mathivet Thomas, Chilov Dmitri, Li Zhilin, Koppinen Tapani, Park Jun-Hee, Fang Shentong, Aspelund Aleksanteri, Saarma Mart, Eichmann Anne, Thomas Jean-Léon, Alitalo Kari
Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Program in Developmental Biology, Institute of Biotechnology, HiLIFE Unit, University of Helsinki, Helsinki, Finland.
J Exp Med. 2017 Dec 4;214(12):3645-3667. doi: 10.1084/jem.20170391. Epub 2017 Nov 15.
The recent discovery of meningeal lymphatic vessels (LVs) has raised interest in their possible involvement in neuropathological processes, yet little is known about their development or maintenance. We show here that meningeal LVs develop postnatally, appearing first around the foramina in the basal parts of the skull and spinal canal, sprouting along the blood vessels and cranial and spinal nerves to various parts of the meninges surrounding the central nervous system (CNS). VEGF-C, expressed mainly in vascular smooth muscle cells, and VEGFR3 in lymphatic endothelial cells were essential for their development, whereas VEGF-D deletion had no effect. Surprisingly, in adult mice, the LVs showed regression after VEGF-C or VEGFR3 deletion, administration of the tyrosine kinase inhibitor sunitinib, or expression of VEGF-C/D trap, which also compromised the lymphatic drainage function. Conversely, an excess of VEGF-C induced meningeal lymphangiogenesis. The plasticity and regenerative potential of meningeal LVs should allow manipulation of cerebrospinal fluid drainage and neuropathological processes in the CNS.
脑膜淋巴管（LVs）的最近发现引发了人们对其可能参与神经病理过程的兴趣，但对其发育或维持情况却知之甚少。我们在此表明，脑膜淋巴管在出生后发育，首先出现在颅底和椎管基部的孔周围，沿着血管以及脑神经和脊神经向中枢神经系统（CNS）周围脑膜的各个部位萌芽生长。主要在血管平滑肌细胞中表达的VEGF-C以及淋巴管内皮细胞中的VEGFR3对其发育至关重要，而VEGF-D缺失则没有影响。令人惊讶的是，在成年小鼠中，VEGF-C或VEGFR3缺失、给予酪氨酸激酶抑制剂舒尼替尼或表达VEGF-C/D陷阱后，淋巴管出现退化，这也损害了淋巴引流功能。相反，过量的VEGF-C会诱导脑膜淋巴管生成。脑膜淋巴管的可塑性和再生潜力应有助于对中枢神经系统中的脑脊液引流和神经病理过程进行调控。
