Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth

The blood and lymphatic vessel networks are jointly essential for development, wound healing and immune surveillance and activation. Pathological responses of these parallel circulatory systems can lead to diseases as varied as age-related macular degeneration, atherosclerosis, cancer, lymphedema, rheumatoid arthritis and tumor metastasis1. Collectively, exuberant or inadequate responses of hemangiogenesis and lymphangiogenesis are estimated to affect nearly two billion people worldwide2,3. The prevalence of such diseases has fueled intense efforts to develop proand antiangiogenic therapeutics. Several antihemangiogenic drugs are US Food and Drug Administration–approved, but, to our knowledge, no lymphangiogenesis-specific inhibitor has yet entered clinical trials. As such, there is great interest in identifying such specific inhibitors both to alleviate disease burden and to better understand lymphatic vascular biology. However, it has been challenging to develop selective approaches toward modulating lymphangiogenesis due to the difficulty in mechanistically disassociating it from hemangiogenesis. The Vegf family of molecules is indispensable for growth of blood4,5 and lymphatic6 vessels. Hemangiogenesis is governed by a precise balance of positive and negative regulators7; however, the mechanisms governing lymphangiogenesis remain nebulous. Soluble VEGFR-1 proteins generated by splice variants in the gene encoding VEGFR-1 act as potent natural inhibitors of hemangiogenesis by trapping the blood endothelial mitogen VEGF-A8–10. To our knowledge, other secreted forms of VEGF tyrosine kinase receptors resulting from splice variants have not been previously reported. Here we describe the detection and function of a new secreted VEGF receptor generated by alternative splicing, which we show is an endogenous antagonist of VEGF-C and a crucial regulator of lymphatic vessel growth. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth