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Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice
Daniela Tirziu, … , Lieve Moons, Michael Simons
Daniela Tirziu, … , Lieve Moons, Michael Simons
Published November 1, 2007
Citation Information: J Clin Invest. 2007;117(11):3188-3197. https://doi.org/10.1172/JCI32024.
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Research Article Article has an altmetric score of 9

Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice

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Abstract

Although studies have suggested a role for angiogenesis in determining heart size during conditions demanding enhanced cardiac performance, the role of EC mass in determining the normal organ size is poorly understood. To explore the relationship between cardiac vasculature and normal heart size, we generated a transgenic mouse with a regulatable expression of the secreted angiogenic growth factor PR39 in cardiomyocytes. A significant change in adult mouse EC mass was apparent by 3 weeks following PR39 induction. Heart weight; cardiomyocyte size; vascular density normalization; upregulation of hypertrophy markers including atrial natriuretic factor, β-MHC, and GATA4; and activation of the Akt and MAP kinase pathways were observed at 6 weeks post-induction. Treatment of PR39-induced mice with the eNOS inhibitor l-NAME in the last 3 weeks of a 6-week stimulation period resulted in a significant suppression of heart growth and a reduction in hypertrophic marker expression. Injection of PR39 or another angiogenic growth factor, VEGF-B, into murine hearts during myocardial infarction led to induction of myocardial hypertrophy and restoration of myocardial function. Thus stimulation of vascular growth in normal adult mouse hearts leads to an increase in cardiac mass.

Authors

Daniela Tirziu, Emmanuel Chorianopoulos, Karen L. Moodie, Robert T. Palac, Zhen W. Zhuang, Marc Tjwa, Carmen Roncal, Ulf Eriksson, Qiangwei Fu, Arye Elfenbein, Amy E. Hall, Peter Carmeliet, Lieve Moons, Michael Simons

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Figure 1

Inducible transgenic PR39/LacZ expression.

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Inducible transgenic PR39/LacZ expression.
(A) β-Galactosidase activity ...
(A) β-Galactosidase activity was induced in Tet-off–inducible MEF/3T3 cells (control) transfected with TRE-PR39/LacZ vector in the absence of doxycycline (ON). In the presence of doxycycline (OFF), β-galactosidase expression was completely abolished. A similar extent of β-galactosidase activity was achieved with the non-inducible reporter vector pCMVβ. (B) RT-PCR analysis of PR39 transcript in mouse hearts. Note expression only in induced tTA+/PR39+ mice (ON) and resuppression of expression by doxycycline (ON/OFF). (C) Hearts of controls and tTA+/PR39+ mice after 3 weeks (top row) and 6 weeks of PR39 induction (middle and bottom rows). Note an increase in the heart size and LV chamber after 6 weeks ON and the extensive expression of the transgene as demonstrated by X-Gal staining (right column). Lower right panel: X-gal–stained LV cross-section. Scale bar: 2 mm; 1 mm (inset). (D and E) Total cardiac endothelial cell mass determined by in vivo anti-PECAM Ab labeling (D) or capillary counting (E). Note a significant increase in endothelial cell mass at week 3 that is maintained at week 6 (n = 5 mice/group). (F) Myocardial endothelial cell mass determined by in vivo anti-PECAM Ab labeling expressed per gram of heart tissue. Note normalization of the endothelial cell mass/g tissue at 6 weeks. (G) Heart weight measurements after 3 and 6 weeks of PR39 induction and 6 weeks ON followed by 3 weeks of suppression (6ON/3OFF), compared with controls. (H) Heart weight/body weight ratio determined after 3 weeks, 6 weeks ON, and 6ON/3OFF. *P < 0.05, **P < 0.01. 3 wk, n = 10 mice/group; 6 wk, n = 16 mice/group; 6ON/3OFF, n = 10 mice/group.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 2 patents
Referenced in 1 clinical guideline sources
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