Catecholamines facilitate VEGF-dependent angiogenesis via β2-adrenoceptor-induced Epac1 and PKA activation
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Jaspal Garg1, Yu-Xi Feng1, Sepp R. Jansen1, Julian Friedrich2, Frank Lezoualc'h3, Martina Schmidt4 and Thomas Wieland1
1Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
25th Medical Clinic, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
3Institute of Cardiovascular and Metabolic Diseases, Inserm UMR-1048, Université Toulouse -Paul Sabatier, Toulouse, France
4Department of Molecular Pharmacology, Center of Pharmacy, University of Groningen, Groningen, The Netherlands
Thomas Wieland, email: [email protected]
Keywords: angiogenesis, cAMP, VEGF, EPAC, PKA
Received: March 24, 2017 Accepted: March 30, 2017 Published: April 20, 2017
Chronic stress has been associated with the progression of cancer and antagonists for β-adrenoceptors (βAR) are regarded as therapeutic option. As they are also used to treat hemangiomas as well as retinopathy of prematurity, a role of endothelial β2AR in angiogenesis can be envisioned. We therefore investigated the role of β2AR-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 β2AR 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, β2AR- 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 β2AR-mediated increase in endothelial VEGFR-2 expression and VEGF secretion.
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