The Dysregulation of Pro-angiogeneic Factors in Pressure-overload Left Ventricular Hypertrophy Results in Inadequate Myocardial Capillarization

Objective: Pressure-overload left ventricular hypertrophy (LVH) as observed in patients with aortic stenosis or arterial hypertension is the most common secondary diagnosis in cardiovascular patients. Untreated LVH is associated to increased myocardial susceptibility to an ischemia-reperfusion injury and results in progressive heart failure due to a vascular insufficiency. We investigated changes in the gene expression of factors related to angiogenesis in a mouse model.

Methods: Myocardial hypertrophy was induced by trans-aortic constriction (TAC) im mice. Hearts were explanted and analyzed for the expression levels of vascular endothelial growth factor (VEGF), its receptors (FLT-1 and KDR) and stromal cell derived factor 1 (SDF-1) as well as the transcription factors hypoxia inducible factor-1 and -2 (HIF-1 and 2) by qPCR compared with sham operated animals over the course of 25 weeks. Histological samples were stained anti-caveolin-1 to visualize and determine the capillary density. The LV-morphology and -function was assessed by ECG-gated MRI weekly.

Results: The heart weight increased statistically significant from week 4 to 25 (p < 0.0001) compared with sham. Compared with controls VEGF expression showed a significant increase for TAC animals after 1 day (2.1x; p < 0.001) and 3 weeks (1.5x; p = 0.014). Similarly, the expression of SDF-1 was increased significantly only at day 1 after TAC (3.1x; p < 0.001). HIF-2 expression was decreased (0.26x; p < 0.0001) 1 week after TAC, followed by a mild increase from week 2 to week 24, but remained significantly lower compared with controls (all p < 0.05). The course of expression levels for receptors FLT-1 and KDR show only moderate changes with a notable expression minimum for FLT-1 after 1 week and a relative maximum at 3 weeks for KDR. After 4 weeks the capillary diameter significantly increased (p < 0.0001) while the capillary density significantly decreased (TAC: 2143 ± 293/mm² versus sham: 2531 ± 321/mm²; p = 0.021). The ejection fraction decreased statistically significant from week 4 (p = 0.049) to week 25 (p = 0.005) compared with sham operated animals.

Conclusion: The decrease in capillary density in hypertrophic myocardium appears to be linked to the dysregulation in the expression of pro-angiogenic factors. Our results show that this dysregulation must be overcome to reconstitute capillary density in the hypertrophic heart, which may improve the myocardial susceptibility to an ischemia-reperfusion injury.