Myocardial β2-adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure

Background and purpose: We investigated whether β(2) -adrenergic receptor (β(2) AR) overexpression could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodeling of the failing heart. Experimental approach: At this aim, we explored the angiogenic effects of β(2) AR overexpression in a rat model of post-myocardial infarction (MI) heart failure (HF). Cardiac adenoviral-mediated β(2) AR overexpression has been obtained via direct intramyocardial injection 4-weeks post-MI. Adenovirus(Ad)-GFP and saline injected rats served as controls. Furthermore, we extended our observation to β(2) AR-/- mice undergoing MI. Key results: Transgenes were robustly expressed in the LV at 2-weeks post gene therapy, whereas their expression was minimal at 4-weeks post-gene delivery. In HF rats, cardiac β(2) AR overexpression resulted in enhanced basal and isoproterenol-stimulated cardiac contractility at 2-weeks post-gene delivery. At 4-weeks post-gene transfer Ad-β(2) AR HF rats showed improved LV remodeling and cardiac function. Importantly, β(2) AR overexpression was associated with markedly increased capillary and arteriolar length density, and enhanced in vivo myocardial blood flow and coronary reserve. At the molecular level, cardiac β(2) AR gene transfer induced the activation of VEGF/Akt/eNOS proangiogenic pathway. In β(2) AR-/- mice, we found a ∼25% reduction of cardiac capillary density compared to β(2) AR+/+ mice. The lack of β(2) AR was associated with higher 30-day mortality rate and LV dilatation, and worse global cardiac contractility compared to controls. Conclusion(s) and implications:β(2) AR plays an important role in the regulation of the angiogenic response in HF. The activation of VEGF/Akt/eNOS pathway seems to be strongly involved in this mechanism.