Kallikrein–Kinin System in Neovascularization

Abstract

T he formation of new blood vessels is viewed completely differently by cardiologists than by oncologists and ophthalmologists. Whereas the former try to stimulate this process, the latter put all efforts into blocking it. In any case, factors involved in neovascularization are of highest therapeutic relevance. The article by Stone et al in this issue of ATVB 1 corroborates that the kallikrein-kinin system (KKS) is one very important but yet underestimated player in this process. This peptide hormone system acts via kinins which are generated from precursors, called kininogens, by enzymes called kallikreins, two of which exist, plasma (PK) and tissue kallikrein (TK). The most important kinin is the nonapeptide bradykinin, which activates the G protein-coupled receptor B2. When kininase I (carboxypeptidase M or N) truncates the peptide by 1 amino acid at the C terminus, the resulting des-Arg 9 bradykinin binds the B1 receptor. Interestingly, this receptor is 1 of the rare G protein-coupled receptors, which is inducible by inflammatory mediators, in contrast to the B2 receptor, which is constitutively expressed in multiple cell types. 2 Kininase II degrades kinins further to inactive fragments and is identical to angiotensin-converting enzyme (ACE). Consequently ACE inhibitors, one of the most popular classes of cardiovascular drugs, not only inhibit angiotensin generation but also stabilize kinins with important consequences in particular in their effects on vessel formation. See accompanying article on page 657The first evidence for a role of the KKS in neovascularization was published already more than 15 years ago. Hu and Fan 3 showed that bradykinin increases angiogenesis in a sponge implantation model through the B1 receptor. This explained earlier puzzling findings showing that angiotensin II as well as ACE inhibitors increase vessel density in several animal models, which seemed paradoxical at first sight. 4,5 Obviously in this case, ACE inhibitors act via the stabilization of kinins and not by the inhibition of angiotensin II generation. 6 Numerous studies have confirmed these findings. Brown-Norway Katholiek rats, which lack secreted kininogen, showed a reduced capacity for new vessel formation in a sponge implantation and in tumor models. 7 When kininogen binding to endothelial cells, the prerequisite for efficient kinin generation by plasma kallikrein, was inhibited either by fragments of the protein or by a specific antibody, new vessel formation was impaired in experimental models 8 and in tumors. 9 Reduced neovascularization was also observed in knockout mice for the B1 receptor using a hindlimb ischemia model 10 and in B2-deficient animals when endothelial cell sprouting was analyzed. 11 The study by Stone et al 1 in this issue adds TK knockout mice to the list of animals with defective neovascularization again using the hindlimb ischemia model. Accordingly, the local overproduction of TK was shown to increase angiogenesis in various situations. 1,[12][13][14] The mechanisms of action of kinins in ...

Angiogenesis Dysregulation in Term Asphyxiated Newborns Treated with Hypothermia

“…While a few studies have found increased VEGF expression in cord blood [ 52 ] and cerebrospinal fluid [ 53 ], others have found either no difference in cerebrospinal fluid VEGF levels between asphyxiated and healthy newborns [ 54 ] or lower serum VEGF expression in severely asphyxiated compared to healthy newborns [ 55 ]. In the present study, KLK-5 expression was reduced in all asphyxiated newborns; KLK-5 promotes extracellular matrix degradation and neovascular sprouting by increasing MMP-9 activity, which, as previously noted, may contribute to brain injury [ 40 , 56 ]. Decreased KLK-5 expression may therefore represent another possible mechanism of neuroprotection or neurorestoration.…”

New topics in bradykinin research

“…In contrast, following ischaemia induced by severing the femoral artery, blood flow was restored after 3 weeks in wt but not in ko-B 1 mice, the latter showing a high incidence of limb necrosis suggesting the B 1 receptor as integral towards promoting neovascularization and angiogenesis (29,30). In another murine model, apolipoprotein (Apo) E and B 1 double ko animals showed a greater incidence of atherosclerotic plaque development and aneurysm than animals with ApoE ko alone, supporting further an antiatherogenic role for kinin B 1 receptors (31).…”

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