Increased vascular permeability in C1 inhibitor–deficient mice mediated by the bradykinin type 2 receptor
Eun D. Han, … , Jennifer Scafidi, Alvin E. Davis III
Eun D. Han, … , Jennifer Scafidi, Alvin E. Davis III
Published April 15, 2002
Citation Information: J Clin Invest. 2002;109(8):1057-1063. https://doi.org/10.1172/JCI14211.
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Article Immunology

Increased vascular permeability in C1 inhibitor–deficient mice mediated by the bradykinin type 2 receptor

Abstract

Heterozygosity for C1 inhibitor (C1INH) deficiency results in hereditary angioedema. Disruption of the C1INH gene by gene trapping enabled the generation of homozygous- and heterozygous-deficient mice. Mating of heterozygous-deficient mice resulted in the expected 1:2:1 ratio of wild-type, heterozygous, and homozygous-deficient offspring. C1INH-deficient mice showed no obvious phenotypic abnormality. However, following injection with Evans blue dye, both homozygous and heterozygous C1INH-deficient mice revealed increased vascular permeability in comparison with wild-type littermates. This increased vascular permeability was reversed by treatment with intravenous human C1INH, with a Kunitz domain plasma kallikrein inhibitor (DX88), and with a bradykinin type 2 receptor (Bk2R) antagonist (Hoe140). In addition, treatment of the C1INH-deficient mice with an angiotensin-converting enzyme inhibitor (captopril) increased the vascular permeability. Mice with deficiency of both C1INH and Bk2R demonstrated diminished vascular permeability in comparison with C1INH-deficient, Bk2R-sufficient mice. These data support the hypothesis that angioedema is mediated by bradykinin via Bk2R.

Authors

Eun D. Han, Ryan C. MacFarlane, Aideen N. Mulligan, Jennifer Scafidi, Alvin E. Davis III

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Genotype/phenotype analysis. (a) The genotype of the C1INH-targeted mice...
Genotype/phenotype analysis. (a) The genotype of the C1INH-targeted mice was determined by PCR amplification using the two primer pairs described in Methods. Amplification in the C1INH+/+ mice resulted in bands of 300 bp and 210 bp; in the C1INH+/– mice, bands of 300 bp, 210 bp, 200 bp, and 150 bp resulted; in the C1INH–/– mice, bands of 200 bp and 150 bp resulted. (b) Detection of C1INH by Western blot analysis of mouse serum using antiserum to mouse C1INH. NEG, negative control; M, molecular weight marker.