Key result
Transaortic constriction cuts myocardial capillary density ~15% vs. sham, linked to proangiogenic dysregulation.
Why the study?
Pressure-overload LVH is an increasingly prevalent condition and independent risk factor for cardiac diseases, prompting investigation into changes in proangiogenic gene expression in a small animal model.
Does transaortic constriction alter the expression of proangiogenic factors and capillary density in a murine model of left-ventricular hypertrophy?
Does transaortic constriction alter the expression of proangiogenic factors and capillary density in a murine model of left-ventricular hypertrophy?
Absolute Event Rate: 2143% vs 2531%
p-value: p=0.021
Pressure-overload hypertrophy leads to a decrease in myocardial capillary density, which appears to be driven by the dysregulation of proangiogenic factors like VEGF and its receptors.
Capillary rarefaction may drive early LV dysfunction in pressure overload; leaves open proangiogenic targeting in human hypertrophy.
Background: Pressure-overload left-ventricular hypertrophy (LVH) is an increasingly prevalent pathological condition of the myocardial muscle and an independent risk factor for a variety of cardiac diseases. We investigated changes in expression levels of proangiogeneic genes in a small animal model of LVH. Methods: Myocardial hypertrophy was induced by transaortic constriction (TAC) in C57BL/6 mice and compared with sham-operated controls. The myocardial expression levels of vascular endothelial growth factor (VEGF), its receptors (KDR and FLT-1), stromal-cell-derived factor 1 (SDF1) and the transcription factors hypoxia-inducible factor-1 and 2 (HIF1 and HIF2) were analyzed by quantitative polymerase chain reaction over the course of 25 weeks. Histological sections were stained for caveolin-1 to visualize endothelial cells and determine the capillary density. The left-ventricular morphology and function were assessed weekly by electrocardiogram-gated magnetic resonance imaging. Results: The heart weight of TAC animals increased significantly from week 4 to 25 ( p = 0.005) compared with sham-treated animals. At 1 day after TAC, the expression of VEGF and SDF1 also increased, but was downregulated again after 1 week. The expression of HIF2 was significantly downregulated after 1 week and remained at a lower level in the subsequent weeks. The expression level of FLT-1 was also significantly decreased 1 week after TAC. HIF-1 and KDR showed similar changes compared with sham-operated animals. However, the expression levels of HIF1 after 4 and 8 weeks were significantly decreased compared with day 1. KDR changes were significantly decreased after 1, 2, 4, 8 and 25 weeks compared with week 3. After 4 weeks post-TAC, the size of the capillary vessels increased ( p = 0.005) while the capillary density itself decreased (TAC: 2143 ± 293 /mm 2 versus sham: 2531 ± 321 /mm 2 ; p = 0.021). Starting from week 4, the left-ventricular ejection fraction decreased compared with controls ( p = 0.049). Conclusions: The decrease in capillary density in the hypertrophic myocardium appears to be linked to the dysregulation in the expression of proangiogeneic factors. The results suggest that overcoming this dysregulation may lead to reconstitution of capillary density in the hypertrophic heart, and thus be beneficial for cardiac function and survival.
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Zeriouh et al. (2019) studied Pressure-overload left-ventricular hypertrophy (n=42). Transaortic constriction (TAC) vs. Sham procedure was evaluated on Capillary density at 4 weeks (p=0.021). Transaortic constriction significantly decreased myocardial capillary density compared to sham operation at 4 weeks (2143 vs 2531 /mm2, p=0.021), linked to dysregulation of proangiogenic factors.
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