Endothelial-cell apoptosis induced by cleaved high-molecular-weight kininogen (HKa) is matrix dependent and requires the generation of reactive oxygen species

Sun, Di; McCrae, Keith R.

doi:10.1182/blood-2005-09-3584

Cited by 24 publications

(16 citation statements)

References 89 publications

(109 reference statements)

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“…Of note, the outcome of the plasma KKS effect on angiogenesis depends not only on a repertoire of endothelial cell membrane proteins (i.e., HK-binding proteins, bound proteases, and receptors) but also on ECM proteins. HKa only induces death of proliferating endothelial cells on permissive surfaces like gelatin, fibronectin, vitronectin, and laminin (640), and its effect on vessel regression depends on the type of collagen (531). Furthermore, compensatory actions of RAS peptides may be integrated in the regulation of angiogenesis by the KKS, since the same enzyme (ACE) upregulates and downregulates the accumulation of proangiogenic ANG II and BK, respectively.…”

Section: Cleaved High-molecular-weight Kininogenmentioning

confidence: 97%

“…An alternative mechanism is the binding of HKa to the cytoskeletal protein tropomyosin (641), which is involved in mediating the antiangiogenic properties of endostatin, an antiangiogenic fragment of collagen XVIII (338). The proposed signaling pathways underlying the antiangiogenic effects of HKa through its D5 region include the disruption of focal adhesions via vitronectin-uPAR-␣v␤3-caveolin-Src-FAK-paxillin (102) or by vitronectin-uPAR-PI3K/Akt-paxillin (277), the reduction of cyclin D1 expression (226), the activation of Cdc2 kinase/cyclin A (597), and the generation of reactive oxygen species dependent on ECM components (531).…”

Section: Cleaved High-molecular-weight Kininogenmentioning

confidence: 99%

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Peptide Hormone Regulation of Angiogenesis

Clapp

Thebault²,

Jeziorski³

et al. 2009

Physiological Reviews

165

158

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It is now apparent that regulation of blood vessel growth contributes to the classical actions of hormones on development, growth, and reproduction. Endothelial cells are ideally positioned to respond to hormones, which act in concert with locally produced chemical mediators to regulate their growth, motility, function, and survival. Hormones affect angiogenesis either directly through actions on endothelial cells or indirectly by regulating proangiogenic factors like vascular endothelial growth factor. Importantly, the local microenvironment of endothelial cells can determine the outcome of hormone action on angiogenesis. Members of the growth hormone/prolactin/placental lactogen, the renin-angiotensin, and the kallikrein-kinin systems that exert stimulatory effects on angiogenesis can acquire antiangiogenic properties after undergoing proteolytic cleavage. In view of the opposing effects of hormonal fragments and precursor molecules, the regulation of the proteases responsible for specific protein cleavage represents an efficient mechanism for balancing angiogenesis. This review presents an overview of the actions on angiogenesis of the above-mentioned peptide hormonal families and addresses how specific proteolysis alters the final outcome of these actions in the context of health and disease.

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Section: Cleaved High-molecular-weight Kininogenmentioning

confidence: 97%

Section: Cleaved High-molecular-weight Kininogenmentioning

confidence: 99%

Peptide Hormone Regulation of Angiogenesis

Clapp

Thebault²,

Jeziorski³

et al. 2009

Physiological Reviews

165

158

View full text Add to dashboard Cite

show abstract

“…152 HKa produced as a result of HK cleavage by plasma kallikrein increases ROS production in a concentrationdependent manner resulting in accelerated senescence of endothelial progenitor cells and endothelial cell apoptosis. 153,154 Bradykin, in addition to stimulating NO production, is also known to induce release of O 2…”

Section: Diabetes Mellitusmentioning

confidence: 99%

Plasma Kallikrein Inhibitors in Cardiovascular Disease

Kolte

Shariat‐Madar

2016

Cardiology in Review

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Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein, and circulates in plasma bound to high molecular weight kininogen. Plasma prekallikrein is activated to plasma kallikrein by activated factor XII or prolylcarboxypeptidase. Plasma kallikrein regulates the activity of multiple proteolytic cascades in the cardiovascular system such as the intrinsic pathway of coagulation, the kallikrein-kinin system, the fibrinolytic system, the renin-angiotensin system, and the complement pathways. As such, plasma kallikrein plays a central role in the pathogenesis of thrombosis, inflammation, and blood pressure regulation. Under physiological conditions, plasma kallikrein serves as a cardioprotective enzyme. However, its increased plasma concentration or hyperactivity perpetuates cardiovascular disease (CVD). In this article, we review the biochemistry and cell biology of plasma kallikrein and summarize data from preclinical and clinical studies that have established important functions of this serine protease in CVD states. Finally, we propose plasma kallikrein inhibitors as a novel class of drugs with potential therapeutic applications in the treatment of CVDs.

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“…HKa did not inhibit endothelial cell function on collagen surfaces (Figure 5B and ref. (18)). Thus, HKa inhibition of tube formation by EPCs in collagen gel reveals a novel mechanism for HKa antiangiogenic activities.…”

Section: Resultsmentioning

confidence: 99%

“…This system without addition of PMA thus allowed us to determine the effects of HKa on EPCs in a more physiologically relevant system. In this modified system, HKa is able to inhibit VEGF-stimulated EPC formation of tubular structures (Figure 5A), whereas HKa inhibition of differentiated endothelial cell function is compromised on 2D collagen surfaces (Figure 5B) (18, 25). Thus, HKa inhibition of tube formation by EPCs in a 3D system reveals its additional activities.…”

Section: Discussionmentioning

confidence: 99%

Cleaved high molecular weight kininogen inhibits tube formation of endothelial progenitor cells via suppression of matrix metalloproteinase 2

Dai

Schmuckler

et al. 2010

Journal of Thrombosis and Haemostasis

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Background and objective Endothelial progenitor cells (EPCs) contribute to postnatal neovascularization, thus promoting wide interest in their therapeutic potential in vascular injury and prevention of their dysfunction in cardiovascular diseases. Cleaved high molecular weight kininogen (HKa), an activation product of the plasma kallikrein-kinin system (KKS), inhibits the functions of differentiated endothelial cells including in vitro and in vivo angiogenesis. In this study, our results provided the first evidence that HKa is able to target EPCs and inhibits their tube forming capacity. Methods and results We determined the effect of HKa on EPCs using a three-dimensional vasculogenesis assay. Upon stimulation with vascular endothelial growth factor (VEGF) alone, EPCs formed vacuoles and tubes, and differentiated into capillary-like networks. As detected by gelatinolytic activity assay, VEGF stimulated secretion and activation of matrix metallopeptidase 2 (MMP-2), but not MMP-9, in the conditioned medium of 3D culture of EPCs. Specific inhibition or gene ablation of MMP-2, but not MMP-9, blocked the vacuole and tube formation by EPCs. Thus, MMP-2 is selectively required for EPC vasculogenesis. In a concentration-dependent manner, HKa significantly inhibited tube formation by EPCs and the conversion of pro-MMP-2 to MMP-2. Moreover, HKa completely blocked the association between pro-MMP- 2 and αvβ3 integrin, and its inhibition of MMP-2 activation was dependent on the presence of αvβ3 integrin. In a purified system, HKa did not directly inhibit MMP-2 activity. Conclusions HKa inhibits tube forming capacity of EPCs by suppression of MMP-2 activation, which may constitute a novel link between activation of the KKS and EPC dysfunction.

show abstract

Endothelial-cell apoptosis induced by cleaved high-molecular-weight kininogen (HKa) is matrix dependent and requires the generation of reactive oxygen species

Cited by 24 publications

References 89 publications

Peptide Hormone Regulation of Angiogenesis

Peptide Hormone Regulation of Angiogenesis

Plasma Kallikrein Inhibitors in Cardiovascular Disease

Cleaved high molecular weight kininogen inhibits tube formation of endothelial progenitor cells via suppression of matrix metalloproteinase 2

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