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

Abstract

AbstractActivation of the transcription factor p53 has been associated with several developmental syndromes. In normal tissues, p53 is kept at very low undetectable physiological levels. When triggered by cellular stressors, p53 prompts important anti-proliferative and apoptotic programs part of its tumor suppressor activity or as the guardian of tissue homeostasis.We generated two murine models that display cutaneous hemorrhaging, severe edema, and distended blood-filled lymphatic vessels at late-gestation due to overactive p53 uniquely affecting lymphatic endothelial cells during development. Overactive p53 operated distinctively through anti-proliferative route in this tissue resulting in a decrease in initial lymphatics that normally absorb interstitial fluid. Remarkably, genetic or pharmacologic normalization of p53 restored lymphatic homeostasis and reversed lymphatic phenotypes. In parallel, several human lymphatic disease tissues exhibited high p53 levels exclusively in the lymphatic endothelium while p53 remained undetectable in surrounding arterial or venous vessels.We report here, for the first time, an extended role that the p53 pathway plays in the genesis of lymphatic homeostasis deficiencies opening the way for new therapeutic avenues for these rare, poorly understood, and incurable lymphatic maladies.