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.
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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Articles in the same Issue
- Masthead
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- Imaging the invisible: resolving cellular microcompartments by superresolution microscopy techniques
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Articles in the same Issue
- Masthead
- Masthead
- Reviews
- Imaging the invisible: resolving cellular microcompartments by superresolution microscopy techniques
- Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases
- Functional ribosome biogenesis is a prerequisite for p53 destabilization: impact of chemotherapy on nucleolar functions and RNA metabolism
- Interleukin-6 and interleukin-11: same same but different
- Cathepsin K: a unique collagenolytic cysteine peptidase
- Research Articles/Short Communications
- Protein Structure and Function
- The active form of goat insulin-like peptide 3 (INSL3) is a single-chain structure comprising three domains B-C-A, constitutively expressed and secreted by testicular Leydig cells
- Molecular Medicine
- Zinc-dependent contact system activation induces vascular leakage and hypotension in rodents
- Cell Biology and Signaling
- ACE inhibition enhances bradykinin relaxations through nitric oxide and B1 receptor activation in bovine coronary arteries
- Changes in COX-2 and oxidative damage factors during differentiation of human mesenchymal stem cells to hepatocyte-like cells is associated with downregulation of P53 gene
- Overexpression of miR-126 promotes the differentiation of mesenchymal stem cells toward endothelial cells via activation of PI3K/Akt and MAPK/ERK pathways and release of paracrine factors
- Novel Techniques
- Synthesis of a novel benzodifuran derivative and its molecular recognition of poly rA RNA