Open AccessPathological hypertrophy reverses β 2 ‐adrenergic receptor‐induced angiogenesis in mouse heart
Author(s) -
Xu Qi,
Jennings Nicole L.,
Sim Kenneth,
Chang Lisa,
Gao XiaoMing,
Kiriazis Helen,
Lee Ying Ying,
Nguyen MyNhan,
Woodcock Elizabeth A.,
Zhang YouYi,
ElOsta Assam,
Dart Anthony M.,
Du XiaoJun
Publication year - 2015
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12340
Subject(s) - angiogenesis , pathological , adrenergic , adrenergic receptor , muscle hypertrophy , medicine , cardiac hypertrophy , receptor , myocardial hypertrophy , endocrinology , bioinformatics , cancer research , biology
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 β 2 ‐adrenoceptors ( β 2 ‐ TG ), and the effect of cardiac pressure overload. β 2 ‐ TG mice had heightened cardiac angiogenesis, which was essential for maintenance of the hypercontractile phenotype seen in this model. Relative to controls, cardiomyocytes of β 2 ‐ TG s 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 β 2 ‐ TG s was inhibited within 1 week after TAC . β 2 ‐ 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 (Ca MKII δ) 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 ‐ TG s 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.