Pressure-induced cardiac overload induces upregulation of endothelial and myocardial progenitor cells

Aim The regulation of angiogenesis in the hypertrophied overloaded heart is incompletely understood. Bone-marrow-derived progenitor cells have been shown to contribute to endothelial homeostasis, repair, and new blood vessel formation. We therefore studied the effects of pressure overload on angiogenesis and progenitor cells. Methods and results Pressure overload induced by transaortic constriction (TAC, C57/B16 mice, 360 mu m for 35 days) increased left ventricular (LV) systolic pressure, the ratio of heart weight to tibia length, cardiomyocyte diameters, and cardiac apoptosis and fibrosis compared to sham-operated mice. In the TAC group, the number of cycling Ki67(pos) cells increased from none to 0.1 +/- 0.02% in cardiomyocytes and from 0.17 +/- 0.02% to 0.65 +/- 0.1% in non-cardiomyocytes, P < 0.001. stem cell antigen 1(pos)/vascular endothelial growth factor receptor 2(pos) endothelial progenitor cells (EPC) increased to 210 +/- 25% in the blood and to 196 +/- 21% in the bone marrow (P < 0.01). TAC upregulated cultured spleen-derived DiLDL(pos)/lectin(pos) EPC to 221 +/- 37%, P < 0.001. Cardiac hypertrophy and upregulation of EPC secondary to cardiac pressure overload were associated with increased extra-cardiac neoangiogenesis (54 +/- 12% increase, P < 0.05). In endothelial nitric oxide synthase double knockout mice, the upregulation of EPIC by TAC was abolished. Maladaptive myocardial remodelling in TAC mice was characterized by a reduction of CD31(pos) cells. In mice transplanted with green fluorescent protein(pos) bone marrow, TAC markedly increased myocardial bone marrow-derived CD31(pos) cells from 2.37 +/- 0.4% to 7.76 +/- 1.5% and MEF2(pos) cells from 1.8 +/- 0.4/mm(2) to 20.5 +/- 5.3/mm(2), P < 0.05. Conclusion Pressure-induced myocardial hypertrophy leads to upregulation of systemic EPCs, increased extra-cardiac angiogenesis, and upregulation of intra-myocardial bone marrow-derived endothelial and myocyte precursor cells. The data show that afterload-dependent regulation of bone marrow-derived progenitor cells contributes to angiogenesis in myocardial hypertrophy.