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Catecholamines facilitate VEGF-dependent angiogenesis via beta2-adrenoceptor-induced Epac1 and PKA activation #MMPMID28512254
Garg J; Feng YX; Jansen SR; Friedrich J; Lezoualc'h F; Schmidt M; Wieland T
Oncotarget 2017[Jul]; 8 (27): 44732-44748 PMID28512254show ga
Chronic stress has been associated with the progression of cancer and antagonists for beta-adrenoceptors (betaAR) are regarded as therapeutic option. As they are also used to treat hemangiomas as well as retinopathy of prematurity, a role of endothelial beta2AR in angiogenesis can be envisioned. We therefore investigated the role of beta2AR-induced cAMP formation by analyzing the role of the cAMP effector molecules exchange factor directly activated by cAMP 1 (Epac1) and protein kinase A (PKA) in endothelial cells (EC). Epac1-deficient mice showed a reduced amount of pre-retinal neovascularizations in the model of oxygen-induced retinopathy, which is predominantly driven by vascular endothelial growth factor (VEGF). siRNA-mediated knockdown of Epac1 in human umbilical vein EC (HUVEC) decreased angiogenic sprouting by lowering the expression of the endothelial VEGF-receptor-2 (VEGFR-2). Conversely, Epac1 activation by beta2AR stimulation or the Epac-selective activator cAMP analog 8-p-CPT-2'-O-Me-cAMP (8-pCPT) increased VEGFR-2 levels and VEGF-dependent sprouting. Similar to Epac1 knockdown, depletion of the monomeric GTPase Rac1 decreased VEGFR-2 expression. As Epac1 stimulation induces Rac1 activation, Epac1 might regulate VEGFR-2 expression through Rac1. In addition, we found that PKA was also involved in the regulation of angiogenesis in EC since the adenylyl cyclase (AC) activator forskolin (Fsk), but not 8-pCPT, increased sprouting in Epac1-depleted HUVEC and this increase was sensitive to a selective synthetic peptide PKA inhibitor. In accordance, beta2AR- and AC-activation, but not Epac1 stimulation increased VEGF secretion in HUVEC.Our data indicate that high levels of catecholamines, which occur during chronic stress, prime the endothelium for angiogenesis through a beta2AR-mediated increase in endothelial VEGFR-2 expression and VEGF secretion.
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Oncotarget 2017 ; 8 (27): 44732-44748
