Abstract 722: Angiogenesis-Driven Myocardial Hypertrophy
Background. Factors determining organ sizes in an adult organism are poorly understood. Previous studies suggest that angiogenesis may be involved in regulation of organ size in the setting of organ repair. However, there is no data regarding the effect of endothelial cell (EC) mass on normal organ size. To address this issue we generated a transgenic mouse with a tetracycline regulatable expression of a secreted angiogenic growth factor (PR39) in heart.
Methods. PR39 expression was induced in cardiac myocytes of 4 –5 week old transgenic mice by doxycycline removal. At pre-specified intervals the heart EC mass was assessed by in vivo radioactive anti-PECAM Ab labeling and capillary density. Hypertrophy was demonstrated by cardiomyocyte size and expression of hypertrophic markers. Cardiac performance was assessed by echocardiography and pressure/volume loop analysis. Littermates not inheriting PR39 gene and subjected to the same conditions served as controls.
Results. PR39 induction in the heart for 3 weeks resulted an increase in EC mass determined by anti-PECAM Ab (0.58 ± 0.04 vs. controls 0.36 ± 0.03 μgAb/g tissue, p < 0.05, n = 5/group) with no changes in heart weight. After 6 weeks of PR39 induction, the heart size increased with 45 % (0.16 vs. controls 0.11g, p < 0.001, n = 16/group). The heart enlargement was accompanied by a 30% increase in cardiomyocyte size, upregulated expression of ANF, βMHC, GATA4, Smad3, skeletal α-actin, tropomyosin 2, calsequestrin and activation of Akt, MAP kinase pathways. The increase in myocardial size resulted in normalization of EC mass: 0.41 ± 0.01 vs. controls 0.37 ± 0.09 μgAb/g tissue, p = NS, n = 5/group. To demonstrate that an increase in EC mass was driving hypertrophy, mice with induced PR39 expression were treated with eNOS inhibitor L-NAME (0.5 g/L). This resulted in a 50% suppression of the increase in heart size and reduced gene expression of hypertrophic markers.
Conclusion. Stimulation of vascular growth in normal adult hearts in the absence of hemodynamic load leads to an increase in cardiac mass paralleled by increment of cardiac performance. This novel mechanism of angiogenesis-driven myocardial hypertrophy may be a fundamental factor regulating the organ size and may provide new avenues for therapeutic strategies.