Abstract
Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed by lymphatic endothelial cells and has been shown to stimulate lymphangiogenesis in adult mice. However, the role VEGFR2 serves in the development of the lymphatic vascular system has not been defined. Here we use the Cre-lox system to show that the proper development of the lymphatic vasculature requires VEGFR2 expression by lymphatic endothelium. We show that Lyve-1wt/Cre;Vegfr2flox/flox mice possess significantly fewer dermal lymphatic vessels than Vegfr2flox/flox mice. Although Lyve-1wt/Cre;Vegfr2flox/flox mice exhibit lymphatic hypoplasia, the lymphatic network is functional and contains all of the key features of a normal lymphatic network (initial lymphatic vessels and valved collecting vessels surrounded by smooth muscle cells (SMCs)). We also show that Lyve-1Cre mice display robust Cre activity in macrophages and in blood vessels in the yolk sac, liver and lung. This activity dramatically impairs the development of blood vessels in these tissues in Lyve-1wt/Cre;Vegfr2flox/flox embryos, most of which die after embryonic day14.5. Lastly, we show that inactivation of Vegfr2 in the myeloid lineage does not affect the development of the lymphatic vasculature. Therefore, the abnormal lymphatic phenotype of Lyve-1wt/Cre;Vegfr2flox/flox mice is due to the deletion of Vegfr2 in the lymphatic vasculature not macrophages. Together, this work demonstrates that VEGFR2 directly promotes the expansion of the lymphatic network and further defines the molecular mechanisms controlling the development of the lymphatic vascular system.
Highlights
The lymphatic vasculature transports immune cells, absorbs dietary fats, and regulates tissue fluid homeostasis by returning fluid and macromolecules to the blood vascular system [1]
We show that the density, but not diameter, of lymphatic vessels is dramatically reduced in Lyve-1wt/Cre;Vegfr2flox/flox mice
We demonstrate that lymphatic vessels in Lyve-1wt/Cre;Vegfr2flox/flox mice properly mature into collecting vessels
Summary
The lymphatic vasculature transports immune cells, absorbs dietary fats, and regulates tissue fluid homeostasis by returning fluid and macromolecules to the blood vascular system [1]. Mutations in VEGF-C, VEGFR3, GJC2, GJA1, KIF11, FOXC2, CCBE1, SOX18, PTPN14, and GATA2 have been found in families with inherited forms of lymphedema and cause striking defects in the development of the lymphatic vasculature [2,3,4,5,6,7,8,9,10,11,12] These important clinical observations have fueled efforts to further identify the molecular mechanisms governing the formation of the lymphatic vasculature. The current model for the development of the mammalian lymphatic vascular system conforms to the centrifugal theory originally proposed by Florence Sabin over 100 years ago [13] According to this model, lymphatic endothelial cells (LECs) differentiate from blood endothelial cells (BECs) and migrate from veins to form lymph sacs during embryogenesis. The molecular mechanisms driving the expansion of the lymphatic network remain largely unknown
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