Abstract 597: TRAIL-TRAIL-R Ligation Regulates EC-pericyte Crosstalk To Generate Stable Microvessel Networks In Ischemia
- Publisher:
- Wolters Kluwer
- Publication Type:
- Journal Article
- Citation:
- Arteriosclerosis Thrombosis and Vascular Biology, 2023, 43, (Suppl_1)
- Issue Date:
- 2023-05
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Endothelial cell EC pericyte crosstalk is essential for generating stable capillary networks Capillary function and development is disrupted in CVD and processes mediating this are poorly understood TNF related apoptosis inducing ligand TRAIL stimulates blood vessel development in pre clinical models while circulating levels are suppressed in CVD patients The contribution of EC specific TRAIL to angiogenesis in ischemia is unknown To address this an EC specific TRAIL knockout Trail EC was generated Compared to Trail EC Trail EC mice had 60 reduction in plasma TRAIL revealing the endothelium as a significant source of TRAIL in the healthy circulation Angiogenesis was quantified in the Matrigel plug aortic sprouting and hindlimb ischemia HLI models EC pericyte content in plugs were 50 60 less in Trail EC than Trail EC mice with a 50 reduction in mRNA expression of angiogenesis pericyte markers Trail EC aortic segments had reduced microvascular sprouts in hypoxia and ECs lacking TRAIL had an impaired ability to form tubules and recruit pericytes CD31 SMA microvessel numbers measure of EC pericyte interaction were significantly reduced in Trail EC ischemic limbs associating with decreased expression of pericyte markers and 50 reduction in blood perfusion Similar findings were observed in Trail receptor Trail R mice In contrast administration of an agonistic anti mouse TRAIL R mAb MD5 1 restored blood perfusion and increased EC pericyte content in ischaemic Trail EC limbs MD5 1 also stimulated aortic sprouts scRNA seq data identified 5 EC clusters 2 of which were markedly altered in Trail EC but not in Trail EC ischemic limbs and multiple EC pericyte interactions dependent on TRAIL were identified In humans TRAIL induces apoptosis through TRAIL R1 and TRAIL R2 Importantly TRAIL and TRAIL R2 mRNA and cell surface expression was augmented and TRAIL physically interacted with TRAIL R2 but not TRAIL R1 under hypoxic conditions These studies provide a novel pathway mediating
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