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Abstract 006: Role of Endothelial YingYang1 in Controlling Angiogenetic Sprouting and Maturation
- Source :
- Arteriosclerosis, Thrombosis, and Vascular Biology. 38
- Publication Year :
- 2018
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2018.
-
Abstract
- Angiogenesis is essential for growth and repair, and irregularity of angiogenesis contributes to numerous malignant, inflammatory and ischemic disorders. Transcription factors that regulate angiogenic gene expression are critical for proper vascular development and homeostasis. Here we show that YingYang1( YY1) is essential for vascular development both in embryonic and postnatal angiogenesis. We first found that endothelium-specific deletion of YY1 leads to embryonic lethality due to vascular defects. We further found inducible endothelial YY1 knockout (YY1 iΔEC ) mice exhibited abnormality of sprouting angiogenesis with a blunted-end, aneurysm-like structure with fewer and dysmorphic filopodia in EC tip cells compared with those of wild-type mice. Similar results are also identified in vitro by using cultured HUVEC cells. Moreover, we found that endothelial deletion of YY1 also leads to severe impairments in retinal vessel remodeling and maturation. Mechanistically, we show that YY1 is a robust endogenous inhibitor of Notch1 signaling that controls explicitly endothelial cell fate. YY1 deficiency remarkably enhances Hey1 expression, resulting in impaired retinal sprouting angiogenesis, which can be rescued by the treatment of the Notch inhibitor. Furthermore, YY1 regulates Hey1 expression by binding to RBP-J via a highly conserved ankyrin (ANK) repeat domain, then inhibits the NICD-MAML1- RBPJ complex formation by competing with MAML1 binding to RBP-J, which attenuates expression of downstream target genes Hey1. Lastly, we found that tumor growth and angiogenesis is reduced significantly in YY1 iΔEC mice, suggesting that endothelial YY1 is required for pathological angiogenesis in mouse tumor models. Altogether, our study reveals a new role for YY1 as a central mediator of Notch signaling and an essential regulator in both physiologic and pathologic angiogenesis.
Details
- ISSN :
- 15244636 and 10795642
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Accession number :
- edsair.doi...........5ec33d5c1a3d8f29dfc918a72d6f9249