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

Erika Terzuoli,Ginevra Nannelli,Federico Corti,Marina Ziche,Antonio Giachetti,Sandra Donnini

doi:10.3390/ijms19092638

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.

Highlights

Inflammation and angiogenesis are closely integrated processes regulating a number of physiological and pathological settings, including wound healing, rheumatoid arthritis, diabetic retinopathy, arteriosclerosis, and cancer [1,2,3]
In order to investigate whether the BK/B2 receptor (B2R) promotes the Fibroblast growth factor-2 (FGF-2)/Fibroblast growth factor receptor-1 (FGFR-1) signaling activation, we determined the FGF-2 expression in human umbilical vein endothelial cells (HUVEC) exposed to BK
In a model of oxygen induced retinopathy (OIR), in mice, we demonstrated that BK/B2R is involved in the pathological retinal neovascularization and that this effect correlated with upregulation of FGF-2 in

Summary

Introduction

Inflammation and angiogenesis are closely integrated processes regulating a number of physiological and pathological settings, including wound healing, rheumatoid arthritis, diabetic retinopathy, arteriosclerosis, and cancer [1,2,3]. Fibroblast growth factor-2 (FGF-2) exerts a key role in the cross-talk between angiogenesis and inflammation by interacting with various surface molecules, including tyrosine kinase receptors Fibroblast growth factor receptor 1 to 4 (FGFR-1 to FGFR-4), heparan-sulfate proteoglycans, integrins and syndecans [4]. In endothelial cells (EC), through the FGFR-1 activation, FGF-2 promotes the inflammatory response during the angiogenic process by inducing vasoactive effects, such as vasodilation and vascular permeability [5,6,7]. We showed that prostaglandin E2 (PGE2) induces angiogenesis by an autocrine FGF-2 mobilization from the EC extracellular matrix, resulting in FGFR-1 signaling activation [12,13]. FGF-2 itself upregulates its expression in EC, and that of other growth factors, including vascular endothelial growth factor (VEGF) [14,15,16]. The EC activation by FGF-2 appears to be a concerted action between an autocrine loop and that of other factors originating in a paracrine modality from inflammatory cells, including prostanoids, cytokines, and other chemokines [17,18]

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Conclusion