Regulation of Angiogenesis by the Kallikrein-Kinin System

Abstract

High molecular weight kininogen (HK) is a plasma protein that is cleaved by plasma kallikrein in the clinical settings of sepsis and chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease. This proteolytic event results in a nonapeptide, bradykinin (BK), and a kinin-free derivative of HK, namely HKa. BK promotes angiogenesis by upregulation of bFGF through the B1 receptor or by stimulation of VEGF formation via the B2 receptor. Kininogen-deficient rats show diminished angiogenesis when neovascularization is stimulated. The formation of HKa results in exposure of domain 5 (D5). HKa or D5 inhibit endothelial cell migration and proliferation, both of which are needed for angiogenesis. In the chicken chorioallantoic membrane assay when neovascularization is stimulated by bFGF or VEGF, HKa or D5 inhibit angiogenesis. Monoclonal antibody C11C1, which prevents binding of HK to endothelial cells, also limits its conversion to BK thus downregulating angiogenesis. In vivo, mAb C11C1 inhibits tumor angiogenesis in mice as well as in experimental inflammatory arthritis and inflammatory bowel disease in Lewis rats. In vitro HKa or D5 inhibits endothelial cell adhesion to vitronectin and fibrinogen, resulting in anokis and apoptosis. The HKa receptor, uPAR, forms a signaling complex containing the integrin alphavbeta3 or alpha5beta1, caveolin, Src kinase Yes, focal adhesion kinase and paxcillin. HKa physically disrupts the complex by interfering with the binding of vitronectin to uPAR. Both mAb C11C1 and D5 have potential applications for controlling unwanted angiogenesis in inflammation and cancer.

Regulatory effects of ferritin on angiogenesis

“…HKa exerts its antiproliferative effects on subconfluent, actively proliferating endothelial cells on a provisional extracellular matrix such as vitronectin (19). We therefore seeded human umbilical vein endothelial cells (HUVEC) onto vitronectin-coated plates at subconfluent density and then either left them untreated or treated them with HKa.…”

Expression, localization and systemic concentration of vascular endothelial growth factor (VEGF) and its receptors in patients with ulcerative colitis

“…The influence of kinins in angiogenesis has recently been appreciated. Kinin promotes angiogenesis by upregulation of basic fibroblast growth factor through bradykinin -B1 receptor and by stimulation of VEGF formation by bradykinin both B1 and B2 receptors [28], and kinins may act synergistically with TGF-β1 [7]. Our recent study [29] strongly indicated that both kinin receptors are present in intestinal layers in human IBD and that B1 receptor is a major structural background for kinin function.…”

Identification of Circulating Natural Antibodies against Endogenous Mediators in the Peripheral Blood Sera of Patients with Osteoarthritis of the Knee: A New Diagnostic Frontier

“…Kinins released into synovial fluid by the proteolytic action of kallikreins on kininogens on the surface of neutrophils are likely to cause vasodilatation and pain, increase vascular permeability, promote leukocyte margination and stimulate cytokine release from monocytes [17,29]. Pain, the predominant symptom in kOA, is multidimensional in its nature and mediated through a variety of factors as bradykinin [30][31][32][33].The RAS is best known as a major regulator of blood pressure, but it also is important at the micro vascular level in the regulation of neovascularization [34,35]. In addition, the RAS has important modulatory activities in the process of kOA [24].…”