VEGF-B Promotes Endocardium-Derived Coronary Vessel Development and Cardiac Regeneration.

Räsänen, Markus; Sultan, Ibrahim; Paech, Jennifer; Hemanthakumar, Karthik Amudhala; Yu, Wei; He, Liqun; Tang, Juan; Sun, Ying; Hlushchuk, Ruslan; Huang, Xiuzhen; Armstrong, Emma; Khoma, Oleksiy-Zakhar; Mervaala, Eero; Djonov, Valentin; Betsholtz, Christer; Zhou, Bin; Kivelä, Riikka; Alitalo, Kari (2021). VEGF-B Promotes Endocardium-Derived Coronary Vessel Development and Cardiac Regeneration. Circulation, 143(1), pp. 65-77. American Heart Association 10.1161/CIRCULATIONAHA.120.050635

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Background: Recent discoveries have indicated that, in the developing heart, sinus venosus and endocardium provide major sources of endothelium for coronary vessel growth that supports the expanding myocardium. Here we set out to study the origin of the coronary vessels that develop in response to vascular endothelial growth factor B (VEGF-B) in the heart and the effect of VEGF-B on recovery from myocardial infarction. Methods: We used mice and rats expressing a VEGF-B transgene, VEGF-B-gene-deleted mice and rats, Apelin (Apln)-CreERT2 and Npr3-CreERT2 recombinase-mediated genetic cell lineage tracing and viral vector-mediated VEGF-B gene transfer in adult mice. Left anterior descending coronary vessel ligation was performed and EdU-mediated proliferating cell cycle labeling, flow cytometry, histological, immunohistochemical, and biochemical methods, single-cell RNA sequencing and subsequent bioinformatic analysis, micro-computed tomography, and fluorescent and tracer-mediated vascular perfusion imaging analyses were used to study the development and function of the VEGF-B-induced vessels in the heart. Results: We show that cardiomyocyte overexpression of VEGF-B in mice and rats during development promotes the growth of novel vessels that originate directly from the cardiac ventricles and maintain connection with the coronary vessels in subendocardial myocardium. In adult mice, endothelial proliferation induced by VEGF-B gene transfer was located predominantly in the subendocardial coronary vessels. Furthermore, VEGF-B gene transduction prior to or concomitantly with ligation of the left anterior descending coronary artery promoted endocardium-derived vessel development into the myocardium and improved cardiac tissue remodeling and cardiac function. Conclusions: The myocardial VEGF-B transgene promotes the formation of endocardium-derived coronary vessels during development, endothelial proliferation in subendocardial myocardium in adult mice, and structural and functional rescue of cardiac tissue after myocardial infarction. VEGF-B could provide a new therapeutic strategy for cardiac neovascularization after coronary occlusion to rescue the most vulnerable myocardial tissue.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy > Topographical and Clinical Anatomy

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Hlushchuk, Ruslan; Khoma, Oleksiy-Zakhar and Djonov, Valentin Georgiev

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1524-4539

Publisher:

American Heart Association

Language:

English

Submitter:

David Christian Haberthür

Date Deposited:

07 Dec 2020 15:39

Last Modified:

01 Jan 2021 01:33

Publisher DOI:

10.1161/CIRCULATIONAHA.120.050635

PubMed ID:

33203221

Uncontrolled Keywords:

cardiac protection

BORIS DOI:

10.7892/boris.148533

URI:

https://boris.unibe.ch/id/eprint/148533

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