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Oliver: Lymphatic Vasculature Formation In Health and Disease

Although the process of blood vasculature formation has been well documented, very little is known about the development of the lymphatic vasculature, despite its importance in normal and pathologic conditions. The lack of specific markers that allow us to monitor the normal and pathologic growth of the lymphatic vasculature has hampered the progress in this field. However, recent identification of genes participating in the formation of the lymphatic vasculature has begun to pave the way toward a new era in which better diagnoses and therapeutic treatment(s) of lymphatic disorders could become a reachable goal.

In addition, more evidences and new animal models confirms the important, but previously not appreciated role of the lymphatics in a variety of functional roles and disorders, such as immune and inflammatory responses, obesity, hypertension and cholesterol control.

Figure 1: The lymphatic vasculature (green) runs parallel to the blood vasculature (red).

An increased understanding of normal lymphatic development should allow us to address pathological lymphatic conditions that lead to inflammation, autoimmunity and cancer, and to improve the clinical treatment of primary and secondary forms of lymphoedema.

We identified the transcription factor Prox1 as the first specific marker of lymphatic endothelial cells, a finding that allowed us to confirm the century-old theory of F. Sabin, who proposed that the mammalian lymphatic vasculature was venous derived (Wigle and Oliver, 1999). We demonstrated that Prox1 is required for the specification of lymphatic progenitor cells in the cardinal vein and that its activity is sufficient to promote lymphatic differentiation in cultured blood endothelial cells (Wigle and Oliver, 1999Wigle et al., 2002Oliver and Detmar, 2002Hong et al., 2002). We have also shown that the lymphatic endothelial cell fate is plastic and reprogrammable and requires constant Prox1 expression for its maintenance (Johnson et al., 2008).

Figure 2: The development of the mammalian lymphatic vasculature starts in the mouse embryo at around E9.75 (A) when a subpopulation of venous endothelial cells start to express Prox1 (green). Few hours later, those cells (blue) start to bud off (B) into the surrounding mesenchyme to form the lymph sacs (C) and eventually the entire lymphatic vasculature (blue in D).

We have also determined that functional inactivation of a single allele of the homeobox gene Prox1 led to adult-onset obesity due to abnormal lymph leakage from mispatterned and ruptured lymphatic vessels (Harvey et al., 2005). Therefore, this is the first report of a novel cause for adult onset obesity as a consequence of lymphatic vasculature defects. Prox1 heterozygous mice are a new model for adult-onset obesity and lymphatic vascular disease.

Figure 3: Prox1 heterozygous mice display late onset obesity.