title: Pathological hypertrophy reverses β2-adrenergic receptor-induced angiogenesis in mouse heart.
abstract: 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 Ca(2+)/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.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Jennings
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Sim
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Chang
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Ying Ying
authors.initials: YY
authors.lastname: Lee
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: My-Nhan
authors.initials: MN
authors.lastname: Nguyen
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Woodcock
authors.affiliation: Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: You-Yi
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Alfred Heart Centre, the Alfred Hospital, Melbourne, Victoria, Australia Central Clinical School, Monash University, Melbourne, Victoria, Australia.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Dart
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Central Clinical School, Monash University, Melbourne, Victoria, Australia xiao-jun.du@bakeridi.edu.au.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
keywords: Angiogenesis; cAMP‐responsive‐element‐binding protein; heart failure; hypertrophy; pressure overload; β2‐adrenoceptor