FOXO1 regulates VEGFA expression and promotes angiogenesis in healing wounds

Hyeran Helen Jeon; Quan Yu; Yongjian Lu; Evelyn Spencer; Chanyi Lu; Tatyana Milovanova; Yang Yang; Chenying Zhang; Olga Stepanchenko; Rameen P Vafa; Paulo G Coelho; Dana T Graves

doi:10.1002/path.5075

FOXO1 regulates VEGFA expression and promotes angiogenesis in healing wounds

J Pathol. 2018 Jul;245(3):258-264. doi: 10.1002/path.5075. Epub 2018 Apr 20.

Authors

Hyeran Helen Jeon^{1

2}, Quan Yu^{2

3}, Yongjian Lu^{2

4}, Evelyn Spencer², Chanyi Lu², Tatyana Milovanova², Yang Yang^{2

5}, Chenying Zhang^{2

6}, Olga Stepanchenko², Rameen P Vafa², Paulo G Coelho^{7

8}, Dana T Graves²

Affiliations

¹ Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Orthodontics, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
⁴ Department of Stomatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
⁵ State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China.
⁶ Department of Preventive Dentistry, Peking University School and Hospital of Stomatology, Beijing, PR China.
⁷ Biomaterials and Biomimetics, College of Dentistry, New York University, New York, NY, USA.
⁸ Hansjörg Wyss Department of Plastic Surgery, Langone Medical Center, New York University, New York, NY, USA.

Abstract

Angiogenesis is a critical aspect of wound healing. We investigated the role of keratinocytes in promoting angiogenesis in mice with lineage-specific deletion of the transcription factor FOXO1. The results indicate that keratinocyte-specific deletion of Foxo1 reduces VEGFA expression in mucosal and skin wounds and leads to reduced endothelial cell proliferation, reduced angiogenesis, and impaired re-epithelialization and granulation tissue formation. In vitro FOXO1 was needed for VEGFA transcription and expression. In a porcine dermal wound-healing model that closely resembles healing in humans, local application of a FOXO1 inhibitor reduced angiogenesis. This is the first report that FOXO1 directly regulates VEGFA expression and that FOXO1 is needed for normal angiogenesis during wound healing. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: FOXO; VEGF; angiogenesis; blood vessel; dermal; endothelial; forkhead; minipig; mucosa; skin; vascular endothelial growth factor-A; wound.

Publication types

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

MeSH terms

Animals
Cell Line
Disease Models, Animal
Female
Forkhead Box Protein O1 / deficiency
Forkhead Box Protein O1 / genetics
Forkhead Box Protein O1 / metabolism*
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism*
Gingiva / injuries
Gingiva / metabolism*
Gingiva / pathology
Humans
Keratinocytes / metabolism
Keratinocytes / pathology
Male
Mice, Knockout
Mouth Mucosa / injuries
Mouth Mucosa / metabolism*
Mouth Mucosa / pathology
Neovascularization, Physiologic*
Signal Transduction
Skin / injuries
Skin / metabolism*
Skin / pathology
Swine
Swine, Miniature
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism*
Wound Healing*
Wounds and Injuries / genetics
Wounds and Injuries / metabolism*
Wounds and Injuries / pathology

Substances

FOXI1 protein, human
Forkhead Box Protein O1
Forkhead Transcription Factors
Foxo1 protein, mouse
VEGFA protein, human
Vascular Endothelial Growth Factor A
vascular endothelial growth factor A, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding