Abstract 1069: Cardiac Overload Is Associated With Cardiac Angiogenesis By Bone Marrow-derived Cells And Upregulation Of Myocyte Precursor Cells
Introduction: The systemic effects of cardiac overload are incompletely understood. Bone marrow-derived progenitor cells have been shown to contribute to endothelial homeostasis, repair and new blood vessel formation. We hypothesized that cardiac overload may induce repair processes mediated by bone marrow-derived cells.
Methods and results: C57Bl/6 mice were lethally irradiated (9Gy) and received GFP-positive bone marrow transplants. Cardiac overload was induced after 4 weeks by transaortic constriction (TAC, 360 μm for 35 days, n=28; SHAM n=15). Some animals received BrdU in the drinking water for 7 days before sacrifice. Left ventricular systolic pressure increased from 67±3 mmHg in sham operated animals to 96±5 mmHg in TAC, p<0.001. The ratio of heart weight to tibia length increased from SHAM 6.9±0.3 to TAC 9.5±0.4, p<0.001 Consistent with hypertrophy, cardiomyocytes (CM) short axis diameter increased from 9.2±0.3 to 12.3±0.3 μm, p<0.0001. To obtain histology data, 11 TAC-mice and 7 Sham mice were examined. TAC increased cardiac fibrosis measured by Sirius Red staining (SHAM 2.7±0.9 %, TAC 9.2±2.2 %, p<0.05). Ki67 and BrdU immunostaining were performed to identify cycling cells. TAC enhanced numbers of Ki67+ CM from 0.02±0.01% to 0.09±0.02% (p<0.05) and BrdU+ CM from 0.003±0.003% to 0.31±0.07% (p<0.01). None of the large, adult Ki67+ or BrdU+ cardiomyocytes positive for α-sarcomeric actin showed GFP staining. Interestingly, staining for MEF2 to detect myocyte precursor cells revealed upregulation of GFP+ bone-marrow derived small MEF2+ cells in the TAC-mice (20.5±5.3/mm2 vs. SHAM 1.9±0.4/mm2, p<0.05). Analysis of the endothelial marker CD31 and co-staining for GFP showed an increase of bone-marrow-derived endothelial cells in hypertrophied myocardium (TAC 7.8±1.5% vs SHAM 2.4±0.4%, p<0.05)
Conclusions: Cardiac afterload in mice increases the number of cardiac endothelial cells and myocyte precursor cells derived from the bone marrow and is associated with the proliferation of cardiomyocytes that are not derived from the bone marrow. Regulation of bone marrow-derived cells may represent an important regulatory effect during cardiac overload.