Vascular Endothelial Growth Factor Blockade Prevents the Beneficial Effects of &bgr;-Blocker Therapy on Cardiac Function, Angiogenesis, and Remodeling in Heart Failure

Background—Impaired angiogenesis in the post-myocardial infarction heart contributes to the progression to heart failure. The inhibition of vascular endothelial growth factor (VEGF) signaling has been shown to be crucial for the transition from compensatory hypertrophy to cardiac failure. Importantly, &bgr;-adrenergic receptor blocker therapy has been also shown to improve myocardial perfusion by enhancing neoangiogenesis in the failing heart. Methods and Results—Eight weeks from surgically induced myocardial infarction, heart failure rats were randomized to receive bisoprolol (B) or vehicle. At the end of a 10-week treatment period, echocardiography revealed reduced cardiac diameters and improved cardiac function in B-treated compared with vehicle-treated rats. Moreover, B treatment was associated with increased cardiac angiogenesis and in vivo coronary perfusion and reduced cardiac fibrosis. Importantly, 2 weeks after B treatment was started, increased cardiac VEGF expression and Akt and endothelial NO synthase activation were observed by comparing B-treated with drug-untreated failing hearts. To test whether the proangiogenic effects of B act via activation of VEGF pathway, 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 with B. After 10 weeks, histological analysis revealed reduced capillary and coronary perfusion in B-treated plus Ad-Flk rats compared with B-treated plus Ad-C rats. Moreover, VEGF inhibition counteracted the positive effects of B on cardiac function and remodeling. Conclusions—&bgr;-Blockade promotes cardiac angiogenesis in heart failure via activation of VEGF signaling pathway. &bgr;-Blocker–induced enhancement of cardiac angiogenesis is essential for the favorable effects of this therapy on cardiac function and remodeling.

[1]  H. Krumholz,et al.  beta-Blocker therapy in heart failure: scientific review. , 2002, JAMA.

[2]  M. Bristow.  β-Adrenergic Receptor Blockade in Chronic Heart Failure , 2000 .

[3]  D. Leosco,et al.  Adrenal GRK2 lowering is an underlying mechanism for the beneficial sympathetic effects of exercise training in heart failure. , 2010, American journal of physiology. Heart and circulatory physiology.

[4]  W. Koch,et al.  Adrenal adrenoceptors in heart failure: fine-tuning cardiac stimulation. , 2007, Trends in molecular medicine.

[5]  R. Bjercke,et al.  Bradycardia-induced coronary angiogenesis is dependent on vascular endothelial growth factor. , 1999, Circulation research.

[6]  P. Anversa,et al.  Myocardial Infarction in Rats: Infarct Size, Myocyte Hypertrophy, and Capillary Growth , 1986, Circulation research.

[7]  Wei Zheng,et al.  Bradycardia Stimulates Vascular Growth During Gradual Coronary Occlusion , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[8]  W. Koch,et al.  Future G protein-coupled receptor targets for treatment of heart failure , 2009, Current treatment options in cardiovascular medicine.

[9]  P. Carmeliet.  Mechanisms of angiogenesis and arteriogenesis , 2000, Nature Medicine.

[10]  B. McConnell,et al.  Acute myocardial infarction in rats. , 2011, Journal of visualized experiments : JoVE.

[11]  D. Leosco,et al.  GRK2 as a novel gene therapy target in heart failure. , 2011, Journal of molecular and cellular cardiology.

[12]  Francesco Prati,et al.  From bench to bedside: a novel technique of acquiring OCT images. , 2008, Circulation journal : official journal of the Japanese Circulation Society.

[13]  P. Gargiulo,et al.  Blockade of β‐adrenoceptors restores the GRK2‐mediated adrenal α2‐adrenoceptor–catecholamine production axis in heart failure , 2012, British journal of pharmacology.

[14]  H. Krumholz,et al.  β-Blocker Therapy in Heart Failure: Scientific Review , 2002 .

[15]  L. Lei,et al.  Bradycardia Induces Angiogenesis, Increases Coronary Reserve, and Preserves Function of the Postinfarcted Heart , 2004, Circulation.

[16]  S. Silver,et al.  Heart Failure , 1937, The New England journal of medicine.

[17]  F. Rengo,et al.  Exercise promotes angiogenesis and improves beta-adrenergic receptor signalling in the post-ischaemic failing rat heart. , 2008, Cardiovascular research.

[18]  F. Rengo,et al.  Prior exercise improves age-dependent vascular endothelial growth factor downregulation and angiogenesis responses to hind-limb ischemia in old rats. , 2007, The journals of gerontology. Series A, Biological sciences and medical sciences.

[19]  R. Weiss,et al.  Postmyocardial infarction remodeling and coronary reserve: effects of ivabradine and beta blockade therapy. , 2009, American journal of physiology. Heart and circulatory physiology.

[20]  R. Henning,et al.  Effects of Ivabradine and Metoprolol on Cardiac Angiogenesis and Endothelial Dysfunction in Rats With Heart Failure , 2009, Journal of cardiovascular pharmacology.

[21]  I. Shiojima,et al.  Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. , 2005, The Journal of clinical investigation.

[22]  E. Olson,et al.  Cardiac hypertrophy: the good, the bad, and the ugly. , 2003, Annual review of physiology.

[23]  D. Leosco,et al.  Myocardial β2‐adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure , 2012, British journal of pharmacology.

[24]  I. Shiojima,et al.  Vascular Endothelial Growth Factor Blockade Promotes the Transition From Compensatory Cardiac Hypertrophy to Failure in Response to Pressure Overload , 2006, Hypertension.

[25]  W. Koch,et al.  Adrenal beta-arrestin 1 inhibition in vivo attenuates post-myocardial infarction progression to heart failure and adverse remodeling via reduction of circulating aldosterone levels. , 2011, Journal of the American College of Cardiology.

[26]  R. Weiss,et al.  Reduction of heart rate by chronic β1-adrenoceptor blockade promotes growth of arterioles and preserves coronary perfusion reserve in postinfarcted heart. , 2005 .

[27]  M. Senni,et al.  [Epidemiology and risk factors for heart failure in the elderly]. , 2004, Italian heart journal : official journal of the Italian Federation of Cardiology.

[28]  D. Leosco,et al.  Targeting the &bgr;-Adrenergic Receptor System Through G-Protein–Coupled Receptor Kinase 2: A New Paradigm for Therapy and Prognostic Evaluation in Heart Failure From Bench to Bedside , 2012, Circulation. Heart failure.

[29]  M. Bristow.  beta-adrenergic receptor blockade in chronic heart failure. , 2000, Circulation.