Abstract 5118: Cardiac β1-Adrenergic Receptor Blockade Promotes Angiogenesis in the Post-Ischemic Failing Heart via Activation of VEGF- and Akt-dependent Signalling Pathways
Impaired angiogenesis in the post-myocardial infarction (MI) heart, contributes to the progression to heart failure (HF). The inhibition of vascular endothelial growth factor (VEGF) signaling has been shown to induce the transition from compensatory hypertrophy to failure. In the present study, we investigated whether treatment with β1- adrenergic receptor (β-AR) blockade Bisoprolol (B) may reactivate VEGF-dependent angiogenesis and counteract maladaptive remodeling in HF. 4 weeks from surgically-induced MI, 40 male Sprague Dawley rats, were randomized to receive B (10 mg/Kg/d, for 10 weeks) or vehicle. 10 sham-operated rats were also included in the study. Echocardiography revealed reduced cardiac LV diameters in B-treated compared to vehicle-treated rats. Moreover, B treatment was associated with increased LV capillary and arteriolar density, and with increased in vivo coronary perfusion and reserve. Importantly, 10 days after B treatment was started, increased cardiac VEGF expression and Akt and eNOS activation were observed by comparing B-treated to drug-untreated hearts. The concomitant administration of B and the mTOR inhibitor Rapamycin (R), which inhibits Akt activation, was associated with increased LV dilatation and dysfunction, and decreased myocardial capillary and arteriolar density compared to B treatment alone. Finally, to test whether the pro-angiogenic effects of B act via activation of VEGF expression, rats were intravenously injected with adenoviral vector encoding a decoy VEGF receptor (Ad-Flk) or a control adenovirus (Ad-C), at the start of the treatment. After 10 weeks from the start of the treatments, histological analysis revealed reduced capillary and arteriolar density, and coronary perfusion in B-treated+Ad-Flk compared to B-treated+Ad-C. Moreover, VEGF inhibition counteracted the positive effects of B on cardiac remodeling and function. In conclusion, β1-AR selective blockade promotes angiogenesis in HF hearts via activation of VEGF- and Akt-dependent signaling pathways. The β-blocker-induced enhancement of vascular bed prevents progression from adaptive to maladaptive remodeling in the failing myocardium, thus counteracting the progressive dysfunction of the failing heart.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).