Age-Associated Loss of Lymphatic Vessels Promotes Cardiac Inflammation (Bulk-RNA-SEQ)
Aging is a major risk factor for cardiovascular diseases, yet the contribution of the lymphatic vasculature to cardiac aging remains largely unexplored. Here, we show that aging reduces lymphatic vessel density in human and mice hearts and induces morphological changes, including the formation of zipper-like, tighter endothelial junctions. These alterations are accompanied by immune cell infiltration, fibrinogen and amyloid accumulation, and myocardial edema. Experimental reduction of cardiac lymphatics in young mice, achieved by Flt4 (VEGFR3) depletion or overexpression of soluble Flt4, reproduces some age-related cardiac phenotypes, such as inflammation and impaired lymphatic integrity. Mechanistically, we found that aging induces the selective up-regulation of nuclear interleukin 33 (IL33) in lymphatic endothelial cells. In contrast to the extracellular, cardioprotective form of IL33, nuclear IL33 promotes lymphatic cell death and junctional remodeling. A targeted screen of pro-lymphatic factors identified VEGFC as an age-sensitive regulator that both declines in the aging heart and suppresses IL33. Cardiac Vegfc overexpression or Il33 silencing restores lymphatic vessel density, reduces macrophage infiltration, and improves tissue homeostasis in aged hearts. Collectively, these findings establish cardiac lymphatic dysfunction and VEGFC deficiency as key features of cardiac aging, highlighting potential therapeutic entry points for age-associated heart disease.
Aging is a major risk factor for cardiovascular diseases, yet the contribution of the lymphatic vasculature to cardiac aging remains largely unexplored. Here, we show that aging reduces lymphatic vessel density in human and mice hearts and induces morphological changes, including the formation of zipper-like, tighter endothelial junctions. These alterations are accompanied by immune cell infiltration, fibrinogen and amyloid accumulation, and myocardial edema. Experimental reduction of cardiac lymphatics in young mice, achieved by Flt4 (VEGFR3) depletion or overexpression of soluble Flt4, reproduces some age-related cardiac phenotypes, such as inflammation and impaired lymphatic integrity. Mechanistically, we found that aging induces the selective up-regulation of nuclear interleukin 33 (IL33) in lymphatic endothelial cells. In contrast to the extracellular, cardioprotective form of IL33, nuclear IL33 promotes lymphatic cell death and junctional remodeling. A targeted screen of pro-lymphatic factors identified VEGFC as an age-sensitive regulator that both declines in the aging heart and suppresses IL33. Cardiac Vegfc overexpression or Il33 silencing restores lymphatic vessel density, reduces macrophage infiltration, and improves tissue homeostasis in aged hearts. Collectively, these findings establish cardiac lymphatic dysfunction and VEGFC deficiency as key features of cardiac aging, highlighting potential therapeutic entry points for age-associated heart disease.