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 (Ca MKIIδ) 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 (₂ AR/ CREB/ VEGF signaling pathway. Pressure overload rapidly inhibited this signaling, likely as a consequence of activated Ca MKII and p53, leading to impaired angiogenesis and functional decompensation. [ABSTRACT FROM AUTHOR]