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Vascular remodeling and the kallikrein-kinin system

Oscar A. Carretero

Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan, USA.

Address correspondence to: Oscar A. Carretero, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202, USA. Phone: (313) 916-2103; Fax: (313) 916-1479; E-mail:

Published March 1, 2005

Remodeling of the arterial wall occurs mainly as a consequence of increased wall stress caused by hypertension. In this issue of the JCI, Azizi et al. report that in humans with a kallikrein gene polymorphism that lowers kallikrein activity, the brachial artery undergoes eutrophic inward remodeling in the absence of hypertension or other hemodynamic changes. It has also been reported that alterations of the kallikrein-kinin system are associated with formation of aortic aneurysms. Conversely, after vascular injury, kinins mediate the beneficial effect of angiotensin-converting enzyme inhibitors that prevent neointima formation. These findings raise the intriguing possibility that decreased kallikrein-kinin system activity may play an important role in the pathogenesis of vascular remodeling and disease, while increased activity may have a beneficial effect.

See the related article beginning on page 780.

Kallikrein-kinin system, vascular expression, and release

Kinins (bradykinin and lysyl-bradykinin) have been implicated in the regulation of renal function, blood flow, and blood pressure (1). The vasodilator, natriuretic, and diuretic effects of kinins are mediated by the release of autacoids such as eicosanoids, NO, and endothelium-derived hyperpolarizing factor. Kinins are released from kininogen by proteolytic enzymes known as kininogenases, the main kininogenases being plasma and tissue (glandular) kallikrein (hereafter referred to as kallikrein). Kinins are rapidly hydrolyzed by a group of peptidases known as kininases (Figure 1). In the blood, kinins circulate in the low picogram range (2–20 pg), a concentration 100 times lower than that needed to decrease blood pressure (2). Thus, if kinins participate in the regulation of blood flow, blood pressure, and renal function, they must act as autocrine hormones (at the site of release) or paracrine hormones (near the site of release) (3).

Mechanism of kinin generation and effect of kinins via various intermediariFigure 1

Mechanism of kinin generation and effect of kinins via various intermediaries (NO, endothelium-derived hyperpolarizing factor [EDHF], and cyclooxygenase- and cytochrome P450–derived eicosanoids).

Kallikrein mRNA and protein are present in blood vessels, which indicates that kallikrein is synthesized in vascular tissue (46). Kallikrein is released from isolated arteries and into the perfusate of isolated rat hindquarters and kidneys (79). While the factors that control vascular kallikrein expression have not been studied in detail, arterial kallikrein is decreased in Goldblatt renovascular hypertensive rats (10). Conversely, in the acute phase of experimental mineralocorticoid/salt hypertension (2 weeks after administration of mineralocorticoid/salt is begun), arterial tissue kallikrein concentration and release are both increased. However, in the chronic phase (4–6 weeks) arterial kallikrein is decreased, while in the veins, tissue kallikrein is increased in both the acute and chronic phase (9). In humans and rats with mineralocorticoid/salt hypertension, renal kallikrein excretion is increased, while in essential hypertension and other types of hypertension, it is decreased (11). Thus expression of kallikrein in the vascular tissue may not necessarily parallel urinary kallikrein excretion.

Kallikrein-kinin system, vascular remodeling, and disease

In this issue of the JCI, Azizi et al. (12) report that subjects with a polymorphism of the human kallikrein gene KLK (R53H) have lower urinary kallikrein excretion compared with that of control subjects (R53R). As a consequence of this polymorphism, the kallikrein expressed has decreased enzymatic activity. Thus, in affected subjects, kallikrein activity should also be decreased in the arterial wall and other tissues, since the polymorphism alters enzymatic activity, not kallikrein expression. In individuals carrying the polymorphism, compared with control subjects, there is a decrease in the internal diameter of the brachial artery but no change in cross-sectional area, a process referred to as eutrophic inward remodeling (Figure 2) (for review, see Mulvany et al.; ref. 13). In these subjects, the arterial wall did not adapt to a chronic increase in shear stress. Azizi et al. indicate that 5–7% of normotensive Caucasian subjects will have the R53H polymorphism and consequently will exhibit eutrophic inward remodeling of the brachial artery. Despite remodeling of the arterial wall and decreased urinary kallikrein enzymatic activity, the subjects had normal blood pressure; however, one of the criteria for inclusion in this study was normotension. Moreover, all of the subjects were young (18–35 years). As individuals with the polymorphism — both the heterozygous (R53H) and the rare homozygous (H53H) form — grow older, it will be extremely interesting to observe whether they develop hypertension or other vascular diseases.

Arterial remodeling. (A) Diagram showing the manner in which remodeling canFigure 2

Arterial remodeling. (A) Diagram showing the manner in which remodeling can modify the cross-sectional area of arteries. The vessel in the center represents a normal artery. Remodeling can be hypotrophic, represented by reduced cross-sectional area of the vessel wall (left); eutrophic, with no change in cross-sectional area (center); or hypertrophic, characterized by increased cross-sectional area (right). These forms of remodeling can be inward, showing decreased lumen diameter (top); or outward, with increased lumen diameter (bottom). Modified with permission from Hypertension (13). (B) Diagram of a normal arterial wall (left) and an arterial wall with eutrophic inward remodeling, showing the decrease in both lumen and external diameter of the artery with normal wall area (right).

The authors recognize that the changes they observed in vascular remodeling could be caused by variations in another gene located at the same site as KLK, and this possibility cannot be ruled out. However, the assumption that the kallikrein-kinin system may play an important role in vascular remodeling and development of vascular disease is also supported by a recent report indicating that kininogen deficiency is associated with aortic aneurysm formation (14). Both kininogen-deficient Brown Norway Katholiek rats (which have a spontaneous mutation in the kininogen gene) and normal Brown Norway rats (which have normal kininogen) are susceptible to development of lesions in the internal elastic lamina of the aorta; however, in that study, a higher proportion of kininogen-deficient rats (50%) developed aneurysms than those with normal kininogen (32%). The aneurysms were associated with enhanced elastolysis, FasL- and caspase-3–mediated apoptosis, induction of MMP-2 and MMP-3 proteolytic cascades, and downregulation of tissue inhibitor of matrix metalloproteinase-4 protein (TIMP-4). Kininogen deficiency was also associated with changes in plasma concentrations of various cytokines. We have reported (15, 16) that carotid neointima formation after endothelial injury was prevented by an angiotensin-converting enzyme or kininase II inhibitor and this effect was mediated by kinins and NO. Furthermore, inactivation of the tissue kallikrein gene in mice induced endothelial dysfunction but not arterial remodeling. However, in these mice, the septum and posterior wall are thinned and left ventricular mass is reduced, while the heart tends to dilate (1719). Collectively, these studies suggest that the cardiovascular kallikrein-kinin system may play a role in arterial and cardiac remodeling and pathology. However, it is very intriguing that these forms of vascular remodeling have a different pathogenesis: (a) eutrophic inward remodeling of the brachial artery, which may be due to restructuring of vascular smooth muscle cells around a smaller lumen as a result of chronic vasoconstriction (20); (b) aortic aneurysms, which may be due to enhanced elastolysis and apoptosis; and (c) neointima formation, which may be due to myofibroblast and vascular smooth muscle cell proliferation and migration to the neointima. Thus, further studies are needed to understand the mechanism by which changes in vascular kallikrein-kinin system activity cause a heterogeneous alteration in the arterial wall and establish whether these changes lead to vascular diseases and hypertension.

Role of the kallikrein-kinin system in sodium and water excretion

Azizi et al. (12) also conclude that despite a 50% deficiency in urinary kallikrein activity in R53H-heterozygous individuals compared with control individuals (R53R), the kidney adapts to large variations in sodium and potassium intake. Although the subjects reach a sodium balance 7 days after being placed on either a low-sodium/high-potassium or high-sodium/low-potassium diet, this is not a very sensitive indicator of whether or not the renal kallikrein-kinin system plays an important role in the regulation of sodium and water excretion. We and others have produced evidence that the renal kallikrein-kinin system contributes to both acute and chronic regulation of water and sodium excretion as well as regulation of renal vascular resistance and medullary blood flow (2123). For example, mice lacking kinin B2 receptors develop hypertension and increased renal vascular resistance after at least 6 weeks of a very high-sodium diet (3.15% Na+ in food plus 1% saline in drinking water) (24). It is beyond the scope of this commentary to discuss the possible role of the renal kallikrein-kinin system in the regulation of renal function (for a review, see ref. 1).

In conclusion, the interesting studies by Azizi et al. (12), reporting remodeling of the brachial artery in human subjects with a polymorphism of the kallikrein gene; Unger’s group (14), reporting increased aneurysm formation in rats deficient in kininogen; and Meneton et al. (17), reporting decreased flow-induced dilatation in kallikrein gene–deficient mice, as well as previous publications regarding vascular kallikrein alterations in hypertension (9, 10), raise the possibility that the genetic association between the genotype R53H and inward remodeling of the brachial artery is causally linked to kallikrein deficiency. These findings also raise the possibility that alterations of the arterial kallikrein-kinin system may play an important role in the pathogenesis of vascular diseases.


See the related article beginning on page 780.

Conflict of interest: The author has declared that no conflict of interest exists.


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