Quinn, K. E. | bioRxiv Science

bioRxiv2024

Lymphatic activation of ACKR3 signaling regulates lymphatic response after ischemic heart injury.

2.BackgroundIschemic heart disease is a prevalent cause of death and disability worldwide. Recent studies reported a rapid expansion of the cardiac lymphatic network upon ischemic heart injury and proposed that cardiac lymphatics may attenuate tissue edema and inflammatory mechanisms after ischemic heart injury. Nevertheless, the mechanisms through which hypoxic conditions affect cardiac lymphangiogenesis and function remain unclear. Here, we aimed to characterize the role of the adrenomedullin decoy receptor atypical chemokine receptor 3 (ACKR3) in the lymphatic response following ischemic heart injury. MethodsSpatial assessment of ACKR3 signaling in the heart after ischemic heart injury was conducted using ACKR3-TangoGFP reporter mice. Roles of ACKR3 after ischemic heart injury were characterized in Ackr3{Delta}Lyve1 mice and in cultured human lymphatic endothelial cells (LECs) exposed to hypoxia. ResultsUsing the novel ACKR3-Tango-GFP reporter mice, we detected activation of ACKR3 signaling in cardiac lymphatics adjacent to the site of ischemic injury of left anterior descending artery (LAD) ligation. Ackr3{Delta}Lyve1 mice exhibited better survival and were protected from the formation of acute tissue edema after ischemic cardiac injury. Ackr3{Delta}Lyve1 mice exhibited a denser cardiac lymphatic network after LAD ligation, especially in the injured tissues. Transcriptomic analysis revealed changes in cardiac lymphatic gene expression patterns that have been associated with extracellular matrix remodeling and immune activation. We also found that ACKR3 plays a critical role in the regulating continuous cell-cell junction dynamics in LECs under hypoxic conditions. ConclusionsLymphatic expression of ACKR3 governs numerous processes following ischemic heart injury, including the lymphangiogenic response, edema protection and overall survival. These results expand our understanding of how the heart failure biomarker adrenomedullin, regulated by lymphatic ACKR3, may exert its cardioprotective roles after ischemic cardiac injury.

physiology↗

bioRxiv2021

Endocardium-to-coronary artery differentiation during heart development and regeneration involves sequential roles of Bmp2 and Cxcl12/Cxcr4.

Regenerating coronary blood vessels has the potential to ameliorate ischemic heart disease, yet there is currently no method of stimulating clinically effective cardiac angiogenesisis. Endocardial cells-- a particularly plastic cell type during development--line the heart lumen and are natural coronary vessel progenitors. Their intrinsic angiogenic potential is lost in adults, but studying the endocardial- to-coronary developmental pathway could identify methods of re-instating this process in diseased hearts. Here, we use a combination of mouse genetics and scRNAseq of lineage-traced endothelial cells to identify novel regulators of endocardial angiogenesis and precisely assess the role of Cxcl12/Cxcr4 signaling. Time-specific lineage tracing demonstrated that endocardial cells differentiated earlier than previously thought, largely at mid-gestation. A new mouse line reporting the activity of Cxcr4 revealed that, despite widespread Cxcl12 and Cxcr4 expression, only a small subset of these coronary endothelial cells activated the receptor, which were mostly in arteries. In accordance with these two findings, Cxcr4 deletion in the endocardial lineage only affected artery formation and only when deleted before mid-gestation. Integrating scRNAseq data of coronary endothelial cells from the endocardial lineage at both mid- and late-gestation identified a transitioning population that was specific to the earlier timepoint that specifically expressed Bmp2. Recombinant Bmp2 stimulated endocardial angiogenesis in an in vitro explant assay and in neonatal mouse hearts upon myocardial infarction. Our data shed light on how understanding the molecular mechanisms underlying endocardial-to-coronary transitions can identify new potential therapeutic targets that could promote revascularization of the injured heart.

developmental biology↗