ABSTRACT
Brain natriuretic peptide (BNP) treatment increases heart function and decreases heart dilation after myocardial infarction. Here, we investigated whether part of the cardioprotective effect of BNP in infarcted hearts related to improved neovascularisation. Infarcted mice were treated with saline or BNP for 10 days. BNP treatment increased vascularisation and the number of endothelial cells in the infarct border and remote zones of infarcted hearts. Endothelial cell lineage tracing showed that BNP directly stimulated the proliferation of resident mature endothelial cells in both areas of the infarcted hearts, via NPR-A binding and p38 MAP kinase activation. BNP also stimulated the proliferation of WT1+ epicardium-derived cells but only in the hypoxic area of infarcted hearts. Our results demonstrated that these immature cells have a natural capacity to differentiate into endothelial cells in infarcted hearts. BNP treatment increased their proliferation but not their differentiation capacity. We identified new roles for BNP and new therapeutic strategies to improve heart recovery in infarcted hearts.
Competing Interest Statement
The authors have declared no competing interest.
CONVENTIONS AND ABBREVIATIONS
- ANP
- atrial natriuretic peptide
- BNP
- brain natriuretic peptide
- BrdU
- 5-Bromo-2′-deoxyuridine
- CNP
- C-type natriuretic peptide
- EndMT
- endothelial-to-mesenchymal transition
- eNOS
- endothelial nitric oxide synthase
- EPDC
- epicardium-derived cell
- FUCCI
- fluorescent ubiquitination-based cell cycle indicator
- GFP
- green fluorescent protein
- HUVEC
- human umbilical vein endothelial cells
- KO
- knockout mouse model
- MI
- myocardial infarction
- NMC
- non-myocyte cells
- NPR-A and NPR-B
- natriuretic peptide receptor A and B
- RZ
- remote zone
- Sca-1
- stem cell antigen 1
- SMA
- smooth muscle actin
- VEGF
- vascular endothelial growth factor
- WT1
- Wilms’ tumour 1 transcription factor
- ZI+BZ
- infarct zone and border zone