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

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

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 6

Cardiac hypertrophy reduction after l-NAME treatment.

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Cardiac hypertrophy reduction after l-NAME treatment....
(A) Cycle GMP production in tTA+/PR39+ and control mouse hearts after 6 weeks of PR39 induction (n = 4 mice/group). (B) Heart weight measurements after 6 weeks of PR39 induction with and without l-NAME treatment (0.5 g/l tap water). l-NAME was given during the last 3 weeks of a 6-week induction period. Note reduction of the increase in heart size caused by PR39 induction (untreated, n = 16 mice/group; l-NAME treated, n = 12 mice/group). (C) RT-PCR analysis of hypertrophy marker expressions in l-NAME–treated versus untreated mice. GAPDH expression used as control. Representative data are shown. Note reduced expression of hypertrophic markers in l-NAME–treated mice. (D) Capillary mass of l-NAME–treated versus untreated mice. (E) Western blot analysis of expression of caveolin-1 (normalized to VE-cadherin) and caveolin-3 (normalized to skeletal α–actinin) after 6 weeks of PR39 induction in the absence or presence of l-NAME (n = 3 mice/group). Note caveolin-1 and -3 expression restoration by l-NAME treatment. (F and G) Effect of l-NAME treatment on LV function. Echocardiographic assessment of posterior wall thickness in diastole in F and LV end-systolic dimension in G. Untreated, n = 15 mice/group; l-NAME treated, n = 6 mice/group. **P < 0.001; *P < 0.05.