Review
Targeting kinin receptors for the treatment of tissue ischaemia

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Abstract

Kinins, the biological end-products of the kallikrein–kininogen system, influence many aspects of the cellular function. Interest in this peptidergic system has been renewed recently by the discovery that kinins exert cardiovascular protective effects and promote post-ischaemic recovery by stimulating vascular growth. Pharmacological and genetic studies indicate that induction of kallikrein and kinin receptors by ischaemia is functionally relevant in the natural host response that permits perfusion recovery and tissue healing. Furthermore, potentiation of the generation of kinins by continuous supply of tissue kallikrein promotes reparative angiogenesis through stimulation of the release of nitric oxide and prostaglandins. Strategies that activate kinin receptors might be applicable to the treatment of occlusive vascular disease, whereas kinin receptor antagonists could represent therapeutic reagents against pathological angiogenesis in cancer and chronic inflammatory conditions.

Section snippets

Expression of the endogenous kallikrein–kinin system in ischaemia

All of the key components of the KKS are present in the vasculature, where it can function by an autocrine and/or paracrine mechanism. TK expression and activity is documented in both human and rat cardiovascular tissue 4, 6. Kinins released from the vascular endothelium activate bradykinin (BK) B1 and B2 receptors on endothelial and vascular smooth muscle cells 4, 7, 8. Binding to B1 and B2 receptors conjointly promotes the formation of prostaglandins and NO, which increases intracellular cAMP

Therapeutic angiogenesis with TK in peripheral ischaemia

Vascular endothelial cells are crucial components of postnatal angiogenesis (Box 2). Because ACE inhibitors can affect endothelial function favourably, it has been hypothesized that their administration might enhance the spontaneous angiogenic response to ischaemia. With this in mind, Fabre et al.22 employed two ACE inhibitors, quinaprilat and captopril, in a rabbit model of limb ischaemia. Although both achieve equivalent levels of ACE inhibition in plasma, only quinaprilat inhibits ACE

Putative mechanisms of TK-induced neoangiogenesis

Various mechanisms that are intrinsic to the biological activities of the KKS are implicated in TK-induced angiogenesis (Fig. 3).

The proteinase activity of TK could activate metalloproteinases type IV collagenase 43 and favour the degradation of the vascular basal membrane and extracellular matrix proteins, an essential step for detachment, invasion and migration of endothelial cells.

TK-generated kinins could evoke plasma-protein extravasation and proliferation of endothelial cells 5, 44, two

Concluding remarks

Recent studies indicate that the KKS has a role in reparative and therapeutic angiogenesis. Thus, local supplementation with TK could benefit the treatment of myocardial and peripheral ischaemia, although additional information regarding the biological impact and safety of TK is necessary before this is applied clinically. For example, although evidence has been provided regarding the magnitude and stability of TK-generated neovascularization, given the complexity of vascular-endothelial-cell

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