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Zinc-dependent contact system activation induces vascular leakage and hypotension in rodents

  • Jenny Björkqvist , Bernd Lecher , Coen Maas and Thomas Renné EMAIL logo
Published/Copyright: May 1, 2013

Abstract

Contact to polyanions induces autoactivation of the serine protease factor XII that triggers the kallikrei-kinin system. Recent studies indicate that polysaccharide-induced autoactivation of factor XII has a role in allergy-related vascular leakage, and angioedema. Here, we characterize in vivo effects of the synthetic polysaccharide dextran sulfate in human plasma and in rodent models. Minute amounts of high-molecular-weight dextran sulfate-initiated factor XII-autoactivation and triggered formation of the inflammatory mediator bradykinin via plasma kallikrein-mediated cleavage of high-molecular-weight kininogen. High-molecular-weight kininogen fragments, containing the HKH20 sequence in domain D5H, blocked dextran sulfate-initiated bradykinin-generation by depleting plasma Zn2+ ions. Topical application of high molecular weight dextran sulfate increased leakage in murine skin microvessels, in a bradykinin-dependent manner. Intravital laser scanning microscopy showed a greater than two-fold elevated and accelerated fluid extravasation in C1 esterase inhibitor deficient mice that lack the major inhibitor of factor XII, compared to wild-type controls. Intra-arterial infusion of dextran sulfate induced a rapid transient drop in arterial blood pressure in rats and preinjection of kinin B2 receptor antagonists or HKH20 peptide blunted dextran sulfate-triggered hypotensive reactions. The data characterize dextran sulfate as a potent in vivo activator of factor XII with implications for bradykinin-mediated vascular permeability and blood pressure control.


Corresponding author: Thomas Renné, MD, PhD, Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; and Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden

This work was supported in part by grants from Vetenskapsrådet (K2013-65X-21462-04-5), Hjärt Lungfonden (20110500), Stockholms läns landsting (ALF 2110471), Cancerfonden (100615), and the ERC StG-2012-311575 grant to TR. CM was supported by a Veni fellowship (016-126-159) from the Netherlands Organization for Scientific Research (NWO). The authors have no conflicting financial interests.

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Received: 2012-10-31
Accepted: 2013-4-24
Published Online: 2013-05-01
Published in Print: 2013-09-01

©2013 by Walter de Gruyter Berlin Boston

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