DIX domain containing 1 (DIXDC1) modulates VEGFR2 level in vasculatures to regulate embryonic and postnatal retina angiogenesis.

Abstract

BACKGROUND:

In sprouting angiogenesis, VEGFR2 level is regulated via a fine-tuned process involving various signaling pathways. Other than VEGF/VEGFR2 signaling pathway, Wnt/ β-catenin signaling is also important in vascular development. However, the crosstalk between these two signaling pathways is still unknown to date. In this study, we aimed to investigate the role of DIX domain containing 1 (DIXDC1) in vasculature, facilitating the crosstalk between VEGF/VEGFR2 and Wnt/ β-catenin signaling pathways.

RESULTS:

In mice, DIXDC1 deficiency delayed angiogenesis at the embryonic stage and suppressed neovascularization at the neonatal stage. DIXDC1 knockdown inhibited VEGF-induced angiogenesis in endothelial cells in vitro by downregulating VEGFR2 expression. DIXDC1 bound Dishevelled Segment Polarity Protein 2 (Dvl2) and polymerized Dvl2 stabilizing VEGFR2 protein via its direct interaction. The complex formation and stability of VEGFR2 was potentiated by Wnt signaling. Moreover, hypoxia elevated DIXDC1 expression and likely modulated both canonical Wnt/β-catenin signaling and VEGFR2 stability in vasculatures. Pathological angiogenesis in DIXDC1 knockout mice was decreased significantly in oxygen-induced retinopathy (OIR) and in wound healing models. These results suggest that DIXDC1 is an important factor in developmental and pathological angiogenesis.

CONCLUSION:

We have identified DIXDC1 as an important factor in early vascular development. These results suggest that DIXDC1 represents a novel regulator of sprouting angiogenesis that links Wnt signaling and VEGFR2 stability and may have a potential role in pathological neovascularization.

• Authors: Yeaji Kim, Dong Young Kim, Haiying Zhang, Cho-Rong Bae, Daehyeon Seong, Yeomyung Kim, Jaewhan Song, Young-Myeong Kim, Young-Guen Kwon
• Journal: BMC biology (BMC Biol) Vol. 20 Issue 1 Pg. 41 (02 10 2022) ISSN: 1741-7007 [Electronic] England
• PMID: 35144597 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Dixdc1 protein, mouse
• Intracellular Signaling Peptides and Proteins
• Vascular Endothelial Growth Factor A
• beta Catenin

Topics

• Animals
• Endothelial Cells (metabolism)
• Intracellular Signaling Peptides and Proteins
• Mice
• Neovascularization, Pathologic (metabolism)
• Retina (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)
• Wnt Signaling Pathway
• beta Catenin (metabolism)