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Signaling Pathway by which β‐adrenoceptor Agonists Enhance Vascular Endothelial Growth Factor Release in Activated Human Macrophages
Author(s) -
Ezeamuzie Charles I.,
ElZohairy Sara,
Oriowo Mabayoje
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.992.1
Subject(s) - u937 cell , atenolol , chemistry , isoprenaline , vascular endothelial growth factor , endocrinology , agonist , medicine , intracellular , pharmacology , signal transduction , monocyte , receptor , microbiology and biotechnology , vegf receptors , biology , in vitro , stimulation , biochemistry , blood pressure
Beta‐adrenoceptor agonists such as salbutamol are valuable bronchodilators, but they can also enhance the release of vascular endothelial growth factor (VEGF), which is capable of inducing tissue remodeling and support inflammation. In this study, we have characterized the signaling pathway involved in the enhancement of VEGF release by β‐adrenoceptor agonists in human macrophages. Human U937 cells differentiated into macrophages were primed with LPS in the absence or presence of β‐adrenoceptor agonists and antagonists. The VEGF released and the intracellular cAMP generated were assayed by ELISA. Isoprenaline, procaterol and salbutamol concentration‐dependently enhanced the release of VEGF induced by LPS in U937 macrophages. They also increased intracellular cAMP levels in these cells. BRL 37344, a selective β3‐adrenoceptor agonist, did not enhance VEGF release. Propranolol, ICI 118551 and atenolol all produced a parallel rightward shift of the isoprenaline dose‐response curve. The −logK B values were 8.12 ± 0.17, 8.03 ± 0.05 and 7.23 ± 0.05, respective, respectively, indicating clear involvement of both β1‐ and β2‐adrenoceptor subtypes. Activators of PKA, but not Epac system, enhanced VEGF release, and this effect was abolished by KT 5720 and Rp‐cAMPS ‐ both selective PKA inhibitors. These results show that β1‐ and β2‐, but not β3‐adrenoceptors, mediate cAMP‐dependent enhancement of VEGF release in LPS‐primed differentiated human U937 macrophages, and that PKA, not Epac, was the downstream effector of cAMP activity. Support or Funding Information This study was funded by Kuwait University Research Sector Grant # YM 14/09.