title: Zinc-dependent contact system activation induces vascular leakage and hypotension in rodents.
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.
authors: Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors: Jenny
authors: J
authors: Björkqvist
authors: Bernd
authors: B
authors: Lecher
authors: Coen
authors: C
authors: Maas
authors: Thomas
authors: T
authors: Renné
mesh_terms: D000818:Animals; D000838:Anions / Q000097:blood; D001920:Bradykinin / Q000097:blood / Q000378:metabolism*; D002199:Capillary Permeability; D016264:Dextran Sulfate / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D005174:Factor XII / Q000378:metabolism; D015956:Factor XIIa / Q000378:metabolism; D006801:Humans; D007022:Hypotension / Q000097:blood* / Q000473:pathology*; D007610:Kallikreins / Q000097:blood / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017208:Rats, Wistar; D015032:Zinc / Q000097:blood* / Q000172:deficiency
chemical_list: D000838:Anions; D005174:Factor XII; D016264:Dextran Sulfate; D007610:Kallikreins; D015956:Factor XIIa; D015032:Zinc; D001920:Bradykinin