Local bradykinin formation is controlled by glycosaminoglycans.
Bradykinin is a potent inflammatory mediator that induces vasodilation, vascular leakage, and pain sensations. This short-lived peptide hormone is liberated from its large precursor protein high molecular weight kininogen (HK) through the contact system cascade involving coagulation factor XII and plasma kallikrein. Although bradykinin release is well established in vitro, the factors and mechanisms controlling bradykinin generation in vivo are still incompletely understood. In this study we demonstrate that binding of HK to glycosaminoglycans (GAGs) of the heparan and chondroitin sulfate type efficiently interferes with bradykinin release in plasma and on endothelial surfaces. Proteolytic bradykinin production on endothelial cells is restored following degradation of cell surface GAG through heparinase. Alternatively, application of HK fragments D3 or light chain, which compete with uncleaved HK for cell binding, promote kininogen proteolysis and bradykinin release. Intravital microscopy revealed that HK fragments increase bradykinin-mediated mesentery microvascular leakage. Topical application of D3 or light chain enhanced bradykinin generation and edema formation in the mouse skin. Our results demonstrate that bradykinin formation is controlled by HK binding to and detachment from GAGs. Separation of the precursor from cell surfaces is a prerequisite for its efficient proteolytic processing. By this means, fragments arising from HK processing propagate bradykinin generation, revealing a novel regulatory level for the kallikrein-kinin system.
Renné
Thomas
T
Institute for Clinical Biochemistry and Pathobiochemistry, Julius-Maximilians-University Wuerzburg, Wuerzburg, Germany. thomas@renne.net
Schuh
Kai
K
Müller-Esterl
Werner
W
D000818:Animals; D001665:Binding Sites; D001920:Bradykinin / Q000096:biosynthesis*; D002199:Capillary Permeability; D004487:Edema / Q000209:etiology; D006025:Glycosaminoglycans / Q000502:physiology*; D019679:Kininogen, High-Molecular-Weight / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
D006025:Glycosaminoglycans; D019679:Kininogen, High-Molecular-Weight; D001920:Bradykinin