Bradykinin B2 Receptor Contributes to Inflammatory Responses in Human Endothelial Cells by the Transactivation of the Fibroblast Growth Factor Receptor FGFR-1

Abstract

Elevated levels of bradykinin (BK) and fibroblast growth factor-2 (FGF-2) have been implicated in the pathogenesis of inflammatory and angiogenic disorders. In angiogenesis, both stimuli induce a pro-inflammatory signature in endothelial cells, activating an autocrine/paracrine amplification loop that sustains the neovascularization process. Here we investigated the contribution of the FGF-2 pathway in the BK-mediated human endothelial cell permeability and migration, and the role of the B2 receptor (B2R) of BK in this cross-talk. BK (1 µM) upregulated the FGF-2 expression and promoted the FGF-2 signaling, both in human umbilical vein endothelial cells (HUVEC) and in retinal capillary endothelial cells (HREC) by the activation of Fibroblast growth factor receptor-1 (FGFR-1) and its downstream signaling (fibroblast growth factor receptor substrate: FRSα, extracellular signal–regulated kinases1/2: ERK1/2, and signal transducer and activator of transcription 3: STAT3 phosphorylation). FGFR-1 phosphorylation triggered by BK was c-Src mediated and independent from FGF-2 upregulation. Either HUVEC and HREC exposed to BK showed increased permeability, disassembly of adherens and tight-junction, and increased cell migration. B2R blockade by the selective antagonist, fasitibant, significantly inhibited FGF-2/FGFR-1 signaling, and in turn, BK-mediated endothelial cell permeability and migration. Similarly, the FGFR-1 inhibitor, SU5402, and the knock-down of the receptor prevented the BK/B2R inflammatory response in endothelial cells. In conclusion, this work demonstrates the existence of a BK/B2R/FGFR-1/FGF-2 axis in endothelial cells that might be implicated in propagation of angiogenic/inflammatory responses. A B2R blockade, by abolishing the initial BK stimulus, strongly attenuated FGFR-1-driven cell permeability and migration.

Platelet-Specific Deletion of Cyclooxygenase-1 Ameliorates Dextran Sulfate Sodium–Induced Colitis in Mice

“…In Vitro Migration and Proliferation Assays. Cell migration of myofibroblasts cultured alone or with platelets was evaluated by scrape-wounding assay, as previously described (Terzuoli et al, 2018). Briefly, after 24 hours of platelet-myofibroblast cocultures, platelets were washed away.…”

Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

“…In COVID-19 patients, the bradykinin–kallikrein pathway may counteract the effects of Ang II on the PAI-1 to tPA/uPA ratio in controlling acute inflammation by increasing the activity of kallikrein, a protease that converts kininogen to bradykinin [ 123 , 124 ]. Bradykinin binds to the bradykinin receptor B2 (B2R) constitutively expressed on endothelial cells [ 123 , 125 ] and is also upregulated in COVID-19 [ 124 ]. It is known that this binding stimulates release of tPA in the human vasculature, which is associated with fibrinolysis and vasodilation [ 124 , 126 ].…”

Subcellular hot spots of GPCR signaling promote vascular inflammation

“…Classically, JAK proteins associate with the cytoplasmic tail of ligand-bound cytokine and growth factor receptors to trigger phosphorylation of STAT family transcription factors, resulting in dimerization, subsequent nuclear translocation and STAT-dependent gene expression that promotes apoptosis, cell migration, and differentiation [ 15 ]. However, bradykinin activation of B2 receptor stimulates extracellular signal regulated kinases-1/2-mediated STAT activation that bridges a positive regulatory loop with the fibroblast growth factor (FGF-2)–FGR1 axis to stimulate endothelial cell barrier disruption and migration [ 16 ]. Interestingly, new work suggests that complement factors promote vascular inflammation via GPCR signaling.…”