Endothelial angiogenesis is directed by RUNX1T1-regulated VEGFA, BMP4 and TGF-β2 expression

Ko-Hsun Liao; Shing-Jyh Chang; Hsin-Chuan Chang; Chen-Li Chien; Tse-Shun Huang; Te-Chia Feng; Wen-Wei Lin; Chuan-Chi Shih; Muh-Hwa Yang; Shung-Haur Yang; Chi-Hung Lin; Wei-Lun Hwang; Oscar K Lee

doi:10.1371/journal.pone.0179758

Endothelial angiogenesis is directed by RUNX1T1-regulated VEGFA, BMP4 and TGF-β2 expression

PLoS One. 2017 Jun 22;12(6):e0179758. doi: 10.1371/journal.pone.0179758. eCollection 2017.

Authors

Ko-Hsun Liao¹, Shing-Jyh Chang², Hsin-Chuan Chang¹, Chen-Li Chien¹, Tse-Shun Huang¹, Te-Chia Feng³, Wen-Wei Lin¹, Chuan-Chi Shih², Muh-Hwa Yang^{4

5

6

7

8}, Shung-Haur Yang^{9

10}, Chi-Hung Lin¹, Wei-Lun Hwang³, Oscar K Lee^{4

11

12

13}

Affiliations

¹ Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
² Department of Obstetrics and Gynecology, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan.
³ The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁴ Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
⁵ Immunity and Inflammation Research Center, National Yang-Ming University, Taipei, Taiwan.
⁶ Cancer Research Center, National Yang-Ming University, Taipei, Taiwan.
⁷ Division of Hematology-Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
⁸ Genomic Research Center, Academia Sinica, Taipei, Taiwan.
⁹ Department of Surgery, Taipei-Veterans General Hospital, Taipei, Taiwan.
¹⁰ School of Medicine, National Yang Ming University, Taipei, Taiwan.
¹¹ Stem Cell Research Center, National Yang-Ming University, Taipei, Taiwan.
¹² Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
¹³ Taipei City Hospital, Taipei, Taiwan.

Abstract

Tissue angiogenesis is intimately regulated during embryogenesis and postnatal development. Defected angiogenesis contributes to aberrant development and is the main complication associated with ischemia-related diseases. We previously identified the increased expression of RUNX1T1 in umbilical cord blood-derived endothelial colony-forming cells (ECFCs) by gene expression microarray. However, the biological relevance of RUNX1T1 in endothelial lineage is not defined clearly. Here, we demonstrate RUNX1T1 regulates the survival, motility and tube forming capability of ECFCs and EA.hy926 endothelial cells by loss-and gain-of function assays, respectively. Second, embryonic vasculatures and quantity of bone marrow-derived angiogenic progenitors are found to be reduced in the established Runx1t1 heterozygous knockout mice. Finally, a central RUNX1T1-regulated signature is uncovered and VEGFA, BMP4 as well as TGF-β2 are demonstrated to mediate RUNX1T1-orchested angiogenic activities. Taken together, our results reveal that RUNX1T1 serves as a common angiogenic driver for vaculogenesis and functionality of endothelial lineage cells. Therefore, the discovery and application of pharmaceutical activators for RUNX1T1 will improve therapeutic efficacy toward ischemia by promoting neovascularization.

MeSH terms

Animals
Blood Vessels / physiology
Bone Morphogenetic Protein 4 / metabolism*
Fetal Blood / cytology
Gene Expression Regulation*
Gene Knockout Techniques
Human Umbilical Vein Endothelial Cells / cytology
Human Umbilical Vein Endothelial Cells / metabolism*
Humans
Mice
Neovascularization, Physiologic*
Proto-Oncogene Proteins / deficiency
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
RUNX1 Translocation Partner 1 Protein
Transcription Factors / deficiency
Transcription Factors / genetics
Transcription Factors / metabolism*
Transforming Growth Factor beta2 / metabolism*
Vascular Endothelial Growth Factor A / metabolism*

Substances

BMP4 protein, human
Bone Morphogenetic Protein 4
Proto-Oncogene Proteins
RUNX1 Translocation Partner 1 Protein
RUNX1T1 protein, human
Transcription Factors
Transforming Growth Factor beta2
VEGFA protein, human
Vascular Endothelial Growth Factor A

Grants and funding

This work is supported by Ministry of Science and Technology (MOST; 104-2321-B-101-027 to S.H.Y; 103-2314-B-010-053-MY3 to O.K.L; 104-0210-01-09-02, and 103-2633-H-010-001 to M.H.Y and 105-2320-B-038-009-MY2 to W.L.H), Yuan’s General Hospital (106YGH-TMU-02 to W.L.H), Hsinchu Mackay Memorial Hospital (MMH-HB-10614 to C.C.S) and Taipei Medical University (TMU104-AE1-B11 to W.L.H).