Unknown,Transcriptomics,Genomics,Proteomics

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Age-Associated Loss of Lymphatic Vessels Promotes Cardiac Inflammation (Bulk-RNA-SEQ)

ABSTRACT: 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.

INSTRUMENT(S): NextSeq 2000

ORGANISM(S): Homo sapiens

SUBMITTER: David John

PROVIDER: E-MTAB-17485 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Inflammatory responses are crucial in the pathological cardiac remodeling and repair after myocardial infarction (MI). The lymphatic endothelial cells (LECs) significantly influence immune cell clearance and mitigate cardiac inflammation. Chemokines are known to tightly regulate immune cell mobilization within the infarcted heart, thereby significantly influencing cardiac inflammation and remodeling. However, the role of chemokines expressed by LECs in the regulation of cardiac inflammation post-MI remains unclear. Our study revealed that the expression of CC chemokine CCL2 in cardiac LECs was sharply un-regulated following MI. We thus hypothesized that lymphatic endothelial CCL2 might be involved in post-MI cardiac remodeling. To test this hypothesis, we generated LEC-conditional Ccl2 knock-out mice. In vivo experiments demonstrated that the LEC-Ccl2 deficiency deteriorated cardiac function and worsened adverse cardiac remodeling after MI. Further analysis showed that the loss of CCL2 in LECs impeded post-MI lymphangiogenesis and increased macrophage infiltration in post-MI myocardium and impaired macrophages clearance via afferent cardiac lymphatics. This led to exacerbated inflammatory responses and pathological cardiac remodeling after MI. Mechanistically, our study identified that LECs expressed and secreted CCL2, which played a dual role. LEC-CCL2 recruit macrophages from the infarcted myocardium into the lymphatic system and activated AKT/ETS1 signaling, enhancing VEGFC expression and promoting lymphangiogenesis in an autocrine manner. This study reveals that cardiac LEC-expressing CCL2 tightly control macrophage trafficking via lymphatic vessels in injured hearts and thus diminished post-MI inflammatory responses and lessened adverse cardiac remodeling. This study demonstrates that CCL2 expression in cardiac LECs tightly controls macrophage trafficking via lymphatic vessels in injured hearts, thereby diminishing post-MI inflammatory responses and lessening adverse cardiac remodeling. This study suggests that modulating CCL2 signaling in LECs could provide a promising therapeutic target for resolving excessive inflammation and ameliorating adverse cardiac remodeling after MI.

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Age-Associated Loss of Lymphatic Vessels Promotes Cardiac Inflammation (Bulk-RNA-SEQ)

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