The p53-p21 axis plays a central role in lymphatic homeostasis and disease

Abstract

The lymphatic system plays important roles in draining fluids from interstitial spaces, absorbing lipids from the intestinal tract, and transporting white blood cells, including antigen-presenting cells, to lymphoid organs. Based on these functions, a number of disorders are associated with lymphatic vascular abnormalities including lymphedema, inflammatory disorders, and tumorassociated lymphangiogenesis. Therefore, understanding the mechanisms underlying the development of the lymphatic network can guide the treatment of lymphatic diseases. Activation of the transcription factor p53 has been implicated in several developmental syndromes where p53 is stimulated by cellular stressors like ribosomal imbalance. Once induced, p53 triggers important anti-proliferative programs like cell-cycle arrest and apoptosis and is therefore maintained at very low physiological levels during embryogenesis. Here, we report for the first time, a critical role of p53 overexpression in defects of lymphatic development. We generated two murine models that carry increased p53 activity induced by ribosomal stress concomitant with the loss of its negative regulators. These high-p53 models are embryonic lethal and present with cutaneous hemorrhaging, severe edema, and distended blood-filled lymphatic vessels. Cellular characterization of the lymphatic endothelial vessels at late-gestation show a reduced proliferation of endothelial cells, upregulation of the growth arrest marker p21 and a potential reduction of initial lymphatics that absorb the interstitial fluid. We also demonstrate that the lymphatic phenotypes are p53-dependent as genetic deletion of one copy of p53 or pharmacologic inhibition of p53 abolishes the cutaneous hemorrhaging, drastically reduces the edema, and rescues the embryonic lethality. Importantly, we detected overexpression of p53 in lymphatic endothelium of lymphedema associated disorders, linking our murine findings to the human disease. Taken together, we discovered that wild type p53 plays a central role in lymphedema predominantly through cell cycle arrest. Our findings indicate that targeting the p53 pathway, an unrecognized mechanism thus far in the genesis of lymphatic deficiencies, may offer therapeutic options for treating incurable lymphatic maladies.