Vascular Endothelial Growth Factor Receptor-2 Promotes the Development of the Lymphatic Vasculature

Abstract

<div><p>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 <i>Cre-lox</i> system to show that the proper development of the lymphatic vasculature requires VEGFR2 expression by lymphatic endothelium. We show that <i>Lyve-1^wt/Cre;Vegfr2^flox/flox</i> mice possess significantly fewer dermal lymphatic vessels than <i>Vegfr2^flox/flox</i> mice. Although <i>Lyve-1^wt/Cre;Vegfr2^flox/flox</i> 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 <i>Lyve-1^Cre</i> mice display robust <i>Cre</i> 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 <i>Lyve-1^wt/Cre;Vegfr2^flox/flox</i> embryos, most of which die after embryonic day14.5. Lastly, we show that inactivation of <i>Vegfr2</i> in the myeloid lineage does not affect the development of the lymphatic vasculature. Therefore, the abnormal lymphatic phenotype of <i>Lyve-1^wt/Cre;Vegfr2^flox/flox</i> mice is due to the deletion of <i>Vegfr2</i> 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.</p></div