BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression

Batya Cohen; Hanoch Tempelhof; Tal Raz; Roni Oren; Julian Nicenboim; Filip Bochner; Ron Even; Adam Jelinski; Raya Eilam; Shifra Ben-Dor; Yoseph Adaddi; Ofra Golani; Shlomi Lazar; Karina Yaniv; Michal Neeman

doi:10.26508/lsa.202000666

BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression

Life Sci Alliance. 2020 Mar 4;3(4):e202000666. doi: 10.26508/lsa.202000666. Print 2020 Apr.

Authors

Batya Cohen¹, Hanoch Tempelhof¹, Tal Raz², Roni Oren¹, Julian Nicenboim¹, Filip Bochner¹, Ron Even¹, Adam Jelinski¹, Raya Eilam³, Shifra Ben-Dor⁴, Yoseph Adaddi⁴, Ofra Golani⁴, Shlomi Lazar⁵, Karina Yaniv⁶, Michal Neeman⁷

Affiliations

¹ Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
² Koret School of Veterinary Medicine, The Hebrew University of Jerusalem, Rehovot, Israel.
³ Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
⁴ Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel.
⁵ Department of Pharmacology, Israel Institute for Biological Research, Ness-Ziona, Israel.
⁶ Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel karina.yaniv@weizmann.ac.il.
⁷ Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel michal.neeman@weizmann.ac.il.

Abstract

Angiogenesis and lymphangiogenesis are key processes during embryogenesis as well as under physiological and pathological conditions. Vascular endothelial growth factor C (VEGFC), the ligand for both VEGFR2 and VEGFR3, is a central lymphangiogenic regulator that also drives angiogenesis. Here, we report that members of the highly conserved BACH (BTB and CNC homology) family of transcription factors regulate VEGFC expression, through direct binding to its promoter. Accordingly, down-regulation of bach2a hinders blood vessel formation and impairs lymphatic sprouting in a Vegfc-dependent manner during zebrafish embryonic development. In contrast, BACH1 overexpression enhances intratumoral blood vessel density and peritumoral lymphatic vessel diameter in ovarian and lung mouse tumor models. The effects on the vascular compartment correlate spatially and temporally with BACH1 transcriptional regulation of VEGFC expression. Altogether, our results uncover a novel role for the BACH/VEGFC signaling axis in lymphatic formation during embryogenesis and cancer, providing a novel potential target for therapeutic interventions.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Modulating Agents / metabolism
Animals
Basic-Leucine Zipper Transcription Factors / genetics*
Basic-Leucine Zipper Transcription Factors / metabolism
Cell Line, Tumor
Fanconi Anemia Complementation Group Proteins / genetics*
Fanconi Anemia Complementation Group Proteins / metabolism
Female
Gene Expression Regulation, Developmental / genetics
Humans
Lymphangiogenesis / physiology
Lymphatic Vessels / metabolism
Mice
Mice, Inbred C57BL
Mice, Nude
Morphogenesis
Neovascularization, Physiologic / physiology*
Signal Transduction
Vascular Endothelial Growth Factor C / genetics*
Vascular Endothelial Growth Factor C / metabolism
Vascular Endothelial Growth Factor Receptor-2 / genetics
Vascular Endothelial Growth Factor Receptor-3 / genetics
Zebrafish / embryology
Zebrafish Proteins / genetics*
Zebrafish Proteins / metabolism

Substances

Angiogenesis Modulating Agents
BACH1 protein, human
Basic-Leucine Zipper Transcription Factors
Fanconi Anemia Complementation Group Proteins
Vascular Endothelial Growth Factor C
Zebrafish Proteins
bach1b protein, zebrafish
Vascular Endothelial Growth Factor Receptor-2
Vascular Endothelial Growth Factor Receptor-3