Molecular and cellular mechanisms of lymphatic vascular maturation

Abstract

Lymphatic vasculature is necessary for maintaining fluid homeostasis in vertebrates. During embryogenesis lymphatic endothelial cells originate from the veins as a homogeneous population. These cells undergo a series of changes at the morphological and molecular levels to become mature lymphatic vasculature that consists of lymphatic capillaries, collecting lymphatic vessels and valves. In this article we summarize our current knowledge about these steps and highlight some black boxes that require further clarification.

Keywords: Blood; Lymph; Lymph sac; Lymphatic capillaries; Lymphatic collecting vessels; Lymphatic endothelial cells; Platelets; Prox1; Smooth muscle cells; Valves.

Figure 1. Development of lymphatic vasculature

A, B) Budding model: LECs originate from the veins as interconnected clusters of cells to maintain vascular integrity. These LECs interact to form the lymph sacs. Platelets likely initiate the separation of blood and lymphatic vasculatures at the lymphovenous valve rudiments. C, D) Ballooning model: LECs form pre lymphatic clusters on the vein which balloon out and inflate to form the lymph sacs. Platelets interact directly with the ballooning LECs and cause the separation between blood and lymphatic vasculatures. A few LECs directly sprout out from the veins. E) LECs sprout from the lymph sacs to form the primitive lymphatic plexus. Subsequent maturation results in lymphatic capillaries and lymphatic collecting vessels. Lymphatic capillaries collect lymph from the interstitium and drain it into the collecting lymphatic vessels. Collecting lymphatic vessels have perivascular cell coverage to propel lymph and valves to prevent regurgitation. Thoracic duct is the longest collecting lymphatic vessel in the mammalian body that returns lymph to the blood circulation via the lymphovenous valves. The proper separation between blood and lymphatic vasculatures is maintained by platelet aggregates at the lymphovenous valves. CV, cardinal vein; LS, lymph sac; IJV, internal jugular vein; SCV, subclavian vein; TD, thoracic duct; LC, lymphatic capillary; VEC, venous endothelial cell; LEC, lymphatic endothelial cell; LECP, lymphatic endothelial cell progenitor; PLC, pre lymphatic cluster; LVV, lymphovenous valve; SMC, smooth muscle cell; LV, lymphatic valve; AF, anchoring filament.

Figure 2. Lymphatic and blood vessels have similar pattern

A) Immunohistochemistry on the peripheral skin of E15.5 embryos using LEC-specific Prox1 (red) and Vegfr3 (green) antibodies. B) Blood vessels in the retina of a 10-days old mouse pup immunostained using PECAM1.