Increasing heart vascularisation after myocardial infarction using brain natriuretic peptide stimulation of endothelial and WT1+ epicardium-derived cells

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. * 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