Bradykinin Signaling Regulates the Vascular Permeability of Lymphatic Endothelial Cells

Introduction:

Some forms of angioedema (AE) – like hereditary angioedema and ACE inhibitor induced AE are mainly mediated by increased levels of the tissue hormone bradykinin (BK). We elucidated the molecular pathways activated by prior BK treatment in lymphatic endothelial cells (EC) to analyze their possible participation in the development of BK-mediated AE.

Methods:

Human dermis microvascular endothelial cells (HDMEC) were characterized by immunofluorescence and fluorescence-activated cell scanning (FACS). Macromolecular permeability assays of HDMEC after BK treatment were performed, as well as analysis of cellular junction proteins, intracellular calcium mobilization and cAMP levels. Furthermore, BK-induced regulation of endothelial destabilizing genes was analyzed by quantitative real-time PCR.

Results:

HDMEC comprise more than 90% lymphatic EC. BK increases the permeability of these cells via BK-2-receptor (B2R) in a dose-dependent manner. BK modifies VE-cadherin phosphorylation and down-regulates claudin-5 expression through B2R. It induces intracellular calcium mobilization, decreases levels of cAMP and up-regulates mRNA levels of endothelial destabilizing genes, vascular endothelial growth factor C (VEGF-C) and angiopoietin-2 (Ang-2).

Conclusions:

Lymphatic EC express B2R and increase their permeability upon BK stimulation. BK-induced B2R signaling in lymphatic EC promotes microvascular homeostasis destabilization by disrupting the endothelial barrier function through modification of cellular junctions and by up-regulating the expression of endothelial permeability inducing target genes VEGF-C and Ang-2.

Publication History

Publication Date:
23 April 2019 (online)