Suppressed angiogenesis in kininogen-deficiencies.
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.
Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan.
Izumi
I
Hayashi
Hideki
H
Amano
Satoko
S
Yoshida
Kazuhisa
K
Kamata
Mariko
M
Kamata
Madoka
M
Inukai
Tomoe
T
Fujita
Yuji
Y
Kumagai
Sen-ichi
S
Furudate
Masataka
M
Majima
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D016228:Endothelial Growth Factors / Q000235:genetics*; D006099:Granuloma / Q000097:blood; D006454:Hemoglobins / Q000378:metabolism; D007704:Kininogens / Q000172:deficiency*; D008222:Lymphokines / Q000235:genetics*; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D011922:Rats, Mutant Strains; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D065168:Bradykinin Receptor Antagonists; D016228:Endothelial Growth Factors; C105311:FR 173657; D006454:Hemoglobins; D007704:Kininogens; D008222:Lymphokines; D011804:Quinolines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D001920:Bradykinin