Back to Search
Start Over
A novel transcriptional complex on the VE-cadherin promoter regulated the downregulation of VE-cadherin in the Down Syndrome Candidate Region 1 isoform 1L-mediated angiogenesis.
- Source :
-
Microvascular Research . Nov2021, Vol. 138, pN.PAG-N.PAG. 1p. - Publication Year :
- 2021
-
Abstract
- Angiogenesis is critical for many diseases. Previously, we reported that Down Syndrome Candidate Region 1 isoform 1L (DSCR1-1L) was one of the most up-regulated genes in endothelial cells induced by VEGF and histamine, and regulated endothelial cell proliferation and Matrigel angiogenesis in mice. However, it was not known whether DSCR1-1L regulated angiogenesis in vivo and what was the molecular mechanism underlying it. In this study, gene knockdown and overexpression models were established to study the role of DSCR1-1L in angiogenesis in vivo. Further, the downstream regulatory target of DSCR1-1L was explored with molecular biological methods in vascular endothelial cells. We found that DSCR1-1L shRNAs significantly inhibited angiogenesis induced by VEGF in mice (p < 0.0001). In the gain-of-function assay, overexpression of DSCR1-1L cDNA in mouse endothelium of EC-FH-DSCR1-1L transgenic mice was sufficient to induce angiogenesis significantly (p < 0.01). DSCR1-1L regulated angiogenesis in the early stage by down-regulation of the VE-cadherin expression through targeting its transcription, but not mRNA stability. Three DSCR1-1L-targeted DNA elements in the VE-cadherin promoter were identified by promoter reporter assays, among which, a novel specific transcriptional complex was found. The DNA sequence (CTTCTG) in the VE-cadherin promoter was identified to directly interact with proteins by Electrophoresis Mobility Shift Assays and DNase I footprint assay. Hence, DSCR1-1L is an excellent therapeutic target for angiogenic diseases through down-regulating the formation of a novel transcriptional complex on the VE-cadherin promoter. DSCR1-1L shRNAs and cDNA have the potential to be developed for clinical application. Our results also contribute significantly to the field of mechanistic studies. • Down Syndrome Candidate Region 1 Isoform 1L shRNAs inhibited angiogenesis in vivo. • overexpression of DSCR1-1L cDNA in mouse endothelium was induce angiogenesis. • DSCR1-1L down-regulated the VE-cadherin transcription, but not mRNA stability. • A novel specific transcriptional complex regulated by DSCR1-1L was found. • The DNA sequence was identified to directly interact with proteins. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00262862
- Volume :
- 138
- Database :
- Academic Search Index
- Journal :
- Microvascular Research
- Publication Type :
- Academic Journal
- Accession number :
- 152393766
- Full Text :
- https://doi.org/10.1016/j.mvr.2021.104209