Activation of cannabinoid receptor type-1 (CB1) and type-2 (CB2) inhibits the release of vascular endothelial growth factor (VEGF-A) from human neutrophils

Abstract

Abstract Background Neutrophils (PMNs) are innate immune cells with primary roles in the acute phase of inflammation and resistance against invading pathogens. Activation of cannabinoid receptor type-1 (CB1) and −2 (CB2) has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. Angiogenesis, the formation of new blood vessels is complex processes that require the coordinated action of several factors, called vascular endothelial growth factors (VEGFs) and angiopoietins (Ang). These factors are produced by several cells, included PMNs. Objective We sought to investigate whether endocannabinoids and their receptors modulate PMNs production of VEGF-A, Ang1, CXCL8 and reactive oxygen species (ROS) production. Methods PMNs were isolated from buffy coats of healthy donors. Cells were stimulated with CB1 and CB2 agonists/antagonists alone and in association with LPS. Mediators concentrations in cell-free supernatants were measured using ELISA, whereas ROS production was evaluated by fluorescence assay. Results CB1 and CB2 agonists did not induce VEGF-A, Ang1 and CXCL8 release from PMNs but reduced spontaneous release of VEGF-A. LPS activated PMNs causing VEGF-A and CXCL8 release. Interestingly, preincubation of PMNs with agonists inhibited in concentration dependent manner VEGF-A release induced by LPS but did not affected CXCL8 production. The effect of CB agonists of LPS induced VEGF-A was reverted by the treatment with CB antagonists. Finally, CB agonists and antagonists promoted ROS production. Conclusions Activation of CB1 and CB2 agonists on PMNs might be a novel strategy to modulate immune cell-assisted angiogenesis.