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

Abstract

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)-CreERT 2 and Npr3-CreERT 2 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.

Endocardium-to-coronary artery differentiation during heart development and regeneration involves sequential roles of Bmp2 and Cxcl12/Cxcr4

“…Future studies should address whether Bmp2 can reactivate endo differentiation in adult hearts, and whether this improves recovery from cardiac injury. Endo angiogenesis has been demonstrated in adult injured hearts overexpressing Vegf-B in CM (Räsänen et al 2021) or Vegfr2 in endo cells (Jiang et al 2021), supporting the idea that adult endo cells do have the potential to differentiate. In total, our findings shed light on the molecular mechanisms orchestrating the cell fate conversion from endo-to-CVs and their role in arterial remodeling.…”

“…The restriction of endo differentiation to embryonic stages is consistent with studies showing that angiogenesis in response to cardiac injury does not normally occur from the endo in neonate and adult hearts (Tang et al 2018;Lu et al 2021). However, some can be induced by Vegf-B or Vegfr2 overexpression after experimental myocardial infarction (MI) (Jiang et al 2021;Räsänen et al 2021). Re-activating endo angiogenesis in adults could be an attractive therapeutic strategy, particularly since ischemic injuries are frequently localized to subendocardial myocardium.…”

Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis

“…Vascular endothelial growth factor (VEGF), a key factor known to stimulate angiogenesis, attenuates cardiac dysfunction after MI in animal models (Cui et al 2018 ; Rasanen et al 2021 ). Previous studies reported that gastrin induced angiogenesis via stimulating VEGF signaling pathway (Bertrand et al 2010 ).…”

Influence of heliogeophysical factors on patients with myocardial infarction

“…For example, during the MS with a C-index of 0.5 out of 206 cases of heart attacks, 127 heart lesions were macrofocal (including transmural), that is, in a percentage ratio of 61.6%; for MSs with a C-index of 1.0 -this figure was 91.2% (54 out of 57) and with a C-index of 1.5 -100%. 12 Ambulance data in the city of Stavropol and materials from the city weather station on SA for 1964 showed that between the relative Wolf number and the frequency of MI related calls, there was an average connection (r + 0.60). The relationship between magnetic activity (K-index) and the occurrence of MI is strong (r + 0.9).…”