Molecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology

Abstract

Lymphangiogenesis refers to the generation of new lymphatic vessels from pre-existing ones. During development and particular adult states, lymphatic endothelial cells (LEC) undergo reprogramming of their transcriptomic and signaling networks to support the high demands imposed by cell proliferation and migration. Although there has been substantial progress in identifying growth factors and signaling pathways controlling lymphangiogenesis in the last decades, insights into the role of metabolism in lymphatic cell functions are just emerging. Despite numerous similarities between the main metabolic pathways existing in LECs, blood ECs (BEC) and other cell types, accumulating evidence has revealed that LECs acquire a unique metabolic signature during lymphangiogenesis, and their metabolic engine is intertwined with molecular regulatory networks, resulting in a tightly regulated and interconnected process. Considering the implication of lymphatic dysfunction in cancer and lymphedema, alongside other pathologies, recent findings hold promising opportunities to develop novel therapeutic approaches. In this review, we provide an overview of the status of knowledge in the molecular and metabolic network regulating the lymphatic vasculature in health and disease.

Targeting lymphatic function in cardiovascular-kidney-metabolic syndrome: preclinical methods to analyze lymphatic function and therapeutic opportunities

“…Enhancement of lymphatic function has the potential to bridge systemic and organ-specific pathologies within CKM syndrome. Restoration of lymphatic function can stabilize metabolite trafficking and attenuate inflammatory processes in metabolic disorders ( 98 , 175 ). Furthermore, lymphatic restoration has the potential to simultaneously improve cardiac and kidney parameters directly.…”

“…Lymphatic anomaly is an umbrella term that includes diseases of lymphatic inactivation, such as primary lymphedema, and lymphatic overactivation, such as malformations ( 59 ). As mentioned previously, primary lymphedema is caused by a deficiency in the lymphatics, commonly congenital, which can manifest as decreased total body coverage, increased lymphatic leakiness, diminished ability to transport lymph, or enhanced inflammation and fibrosis ( 98 ). Primary lymphedema is the result of insufficient lymphatics and lymph absorption, which makes it an enticing indication to translate therapeutic targets into models of CKM syndrome.…”