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.

Shiqiang Hou, Gengming Niu, Xin Liu, Pierre M Bourbon, Dongmei Zhang, Pengfei Cui, Kevin Zhao, Dezheng Zhao, Huiyan Zeng

Microvascular research 2021 Nov

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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. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Shiqiang Hou, Gengming Niu, Xin Liu, Pierre M Bourbon, Dongmei Zhang, Pengfei Cui, Kevin Zhao, Dezheng Zhao, Huiyan Zeng. 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. Microvascular research. 2021 Nov;138:104209