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Cardiovascular Research Advance Access first published online on October 13, 2007
This version [Corrected Proof] published online on November 12, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm037
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Pressure-induced cardiac overload induces upregulation of endothelial and myocardial progenitor cells

Patrick Müller*,{dagger}, Andrey Kazakov{dagger}, Alexander Semenov, Michael Böhm and Ulrich Laufs

Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66424 Homburg/Saar, Germany

* Corresponding author. Tel: +49 6841 162 3372; fax: +49 6841 162 3434. E-mail address: pamue{at}med-in.uni-sb.de

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/Bl6 mice, 360 µm 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 Ki67pos 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 1pos/vascular endothelial growth factor receptor 2pos 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 DiLDLpos/lectinpos 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 EPC by TAC was abolished. Maladaptive myocardial remodeling in TAC mice was characterized by a reduction of CD31pos cells. In mice transplanted with green fluorescent proteinpos bone marrow, TAC markedly increased myocardial bone marrow-derived CD31pos cells from 2.37 ± 0.4% to 7.76 ± 1.5% and MEF2pos cells from 1.8 ± 0.4/mm2 to 20.5 ± 5.3/mm2, 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.

KEYWORDS myocardial hypertrophy; endothelial progenitor cells; angiogenesis; transgenic animal models; nitric oxide

Time for primary review: 35 days

{dagger} P.M and A.K contributed equally to this study and share first authorship


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