Suppressed Angiogenesis in Kininogen-Deficiencies

Abstract

SUMMARY:We investigated whether the kinin-generating system enhanced angiogenesis in chronic and proliferative granuloma and in tumor-surrounding stroma. In rat sponge implants, angiogenesis was gradually developed in normal Brown Norway Kitasato rats (BN-Ki). The development of angiogenesis was significantly suppressed in kininogen-deficient Brown Norway Katholiek rats (BN-Ka). The angiogenesis enhanced by basic fibroblast growth factor was also significantly less marked in BN-Ka than in BN-Ki. Naturally occurring angiogenesis was significantly suppressed by B 1 or B 2 antagonist. mRNA of vascular endothelial growth factor was more highly expressed in the granulation tissues in BN-Ki than in BN-Ka. Daily topical injections of aprotinin, but not of soy bean trypsin inhibitor, suppressed angiogenesis. Daily topical injections of low-molecular weight kininogen enhanced angiogenesis in BN-Ka. Topical injections of serum from BN-Ki, but not from BN-Ka, also facilitated angiogenesis in BN-Ka. FR190997, a nonpeptide mimic of bradykinin, promoted angiogenesis markedly, with concomitant increases in vascular endothelial growth factor mRNA. Angiogenesis in the granulation tissues around the implanted Millipore chambers containing Walker-256 cells was markedly more suppressed in BN-Ka than in BN-Ki. Our results suggest that endogenous kinin generated from the tissue kallikrein-kinin system enhances angiogenesis in chronic and proliferative granuloma and in the stroma surrounding a tumor. Thus, the agents for the kinin-generating system and/or kinin receptor signaling may become useful tools for controlling angiogenesis. (Lab Invest 2002, 82:871-880).

Roles of Prostaglandin E 2 –EP3/EP4 Receptor Signaling in the Enhancement of Lymphangiogenesis During Fibroblast Growth Factor-2–Induced Granulation Formation

“…In the sponge model, granulation tissues with the property of chronic inflammation were formed around the sponge implants with enough reproducibility, and we can easily determine the active molecules at the site of the chronic inflammation, because rapid sampling and easy extractions of active molecules and mRNA can be performed in the sponge model. The results with this sponge model have been published in some journals, 5,6,26,27,29,[31][32][33][34][35][36][37][38][39][40] and many researchers have a strong interest in this model. In the beginning of this study, we had tried to test this sponge model to clarify the involvement of PGs in lymphangiogenesis during the chronic inflammation, but the detection of newly developed lymphatics was quite difficult in the sponge model.…”

High-Molecular-Weight Kininogen Fragments Stimulate the Secretion of Cytokines and Chemokines Through uPAR, Mac-1, and gC1qR in Monocytes

“…The finding that rats deficient in kininogen have impaired angiogenic responses 25 is easily explained by the lack of BK, a potent angiogenic stimulus. But the decrease in the response of HK-deficient Lewis rats to the ability of proteoglycanpolysaccharides to induce inflammatory arthritis 26 and inflammatory bowel disease 27 is difficult to rationalize based on the known actions of BK.…”

Deletion of murine kininogen gene 1 (mKng1) causes loss of plasma kininogen and delays thrombosis

“…14 Angiogenesis has been reported to be diminished in Brown-Norway Katholiek rats, in which a spontaneous mutation in the kininogen gene causes deficient kininogen secretion and reduced plasma kininogen levels. 15 However, a murine model of kininogen deficiency is not presently available. To develop such a model, we characterized the murine kininogen gene, finding that the murine genome contains 2 homologous copies of this gene located in a head-to-head orientation on chromosome 16.…”