Pathological hypertrophy reverses β2‐adrenergic receptor‐induced angiogenesis in mouse heart

β‐adrenergic activation and angiogenesis are pivotal for myocardial function but the link between both events remains unclear. The aim of this study was to explore the cardiac angiogenesis profile in a mouse model with cardiomyocyte‐restricted overexpression of β2‐adrenoceptors (β2‐TG), and the effect of cardiac pressure overload. β2‐TG mice had heightened cardiac angiogenesis, which was essential for maintenance of the hypercontractile phenotype seen in this model. Relative to controls, cardiomyocytes of β2‐TGs showed upregulated expression of vascular endothelial growth factor (VEGF), heightened phosphorylation of cAMP‐responsive‐element‐binding protein (CREB), and increased recruitment of phospho‐CREB, CREB‐binding protein (CBP), and p300 to the VEGF promoter. However, when hearts were subjected to pressure overload by transverse aortic constriction (TAC), angiogenic signaling in β2‐TGs was inhibited within 1 week after TAC. β2‐TG hearts, but not controls, exposed to pressure overload for 1–2 weeks showed significant increases from baseline in phosphorylation of Ca2+/calmodulin‐dependent kinase II (CaMKIIδ) and protein expression of p53, reduction in CREB phosphorylation, and reduced abundance of phospho‐CREB, p300 and CBP recruited to the CREB‐responsive element (CRE) site of VEGF promoter. These changes were associated with reduction in both VEGF expression and capillary density. While non‐TG mice with TAC developed compensatory hypertrophy, (2‐TGs exhibited exaggerated hypertrophic growth at week‐1 post‐TAC, followed by LV dilatation and reduced fractional shortening measured by serial echocardiography. In conclusion, angiogenesis was enhanced by the cardiomyocyte (2AR/CREB/VEGF signaling pathway. Pressure overload rapidly inhibited this signaling, likely as a consequence of activated CaMKII and p53, leading to impaired angiogenesis and functional decompensation