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. 2013 May 13:4:111.
doi: 10.3389/fimmu.2013.00111. eCollection 2013.

Role of arginase in vessel wall remodeling

William Durante  1
Affiliations

Role of arginase in vessel wall remodeling

William Durante. Front Immunol. .

Abstract

Arginase metabolizes the semi-essential amino acid l-arginine to l-ornithine and urea. There are two distinct isoforms of arginase, arginase I and II, which are encoded by separate genes and display differences in tissue distribution, subcellular localization, and molecular regulation. Blood vessels express both arginase I and II but their distribution appears to be cell-, vessel-, and species-specific. Both isoforms of arginase are induced by numerous pathologic stimuli and contribute to vascular cell dysfunction and vessel wall remodeling in several diseases. Clinical and experimental studies have documented increases in the expression and/or activity of arginase I or II in blood vessels following arterial injury and in pulmonary and arterial hypertension, aging, and atherosclerosis. Significantly, pharmacological inhibition or genetic ablation of arginase in animals ameliorates abnormalities in vascular cells and normalizes blood vessel architecture and function in all of these pathological states. The detrimental effect of arginase in vascular remodeling is attributable to its ability to stimulate vascular smooth muscle cell and endothelial cell proliferation, and collagen deposition by promoting the synthesis of polyamines and l-proline, respectively. In addition, arginase adversely impacts arterial remodeling by directing macrophages toward an inflammatory phenotype. Moreover, the proliferative, fibrotic, and inflammatory actions of arginase in the vasculature are further amplified by its capacity to inhibit nitric oxide (NO) synthesis by competing with NO synthase for substrate, l-arginine. Pharmacologic or molecular approaches targeting specific isoforms of arginase represent a promising strategy in treating obstructive fibroproliferative vascular disease.

Keywords: arginase; endothelial dysfunction; nitric oxide; smooth muscle cell proliferation; vascular remodeling.

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Figures

Figure 1
Figure 1
Regulation of l-arginine metabolism by vascular cells. NO, nitric oxide; NOS, nitric oxide synthase; ASS, argininosuccinate synthetase; ASL, argininosuccinate lyase; ADC, arginine decarboxylase; ODC, ornithine decarboxylase; OAT, ornithine aminotransferase; P5C, pyrroline-5-carboxylate; P5CR, pyrroline-5-carboxylate reductase.
Figure 2
Figure 2
Model for the regulation of vascular remodeling by arginase in arterial injury, pulmonary arterial hypertension (PAH), arterial hypertension, and aging. Arterial injury, PAH, arterial hypertension, and aging stimulates the activity and/or expression of arginase I or II in blood vessels, while arterial injury and aging also stimulates the expression of inducible nitric oxide (NO) synthase (iNOS). The induction of iNOS by aging or arterial injury may further augment the activation of arginase I by nitrosylating a specific cysteine residue of the enzyme. Activation or induction of both arginase isoforms stimulate vascular smooth muscle cell (SMC) and endothelial cell (EC) proliferation, and collagen synthesis by increasing the production of polyamines and l-proline. These cellular actions of arginase are further amplified by the ability of arginase to limit the metabolism of l-arginine by iNOS and endothelial NO synthase (eNOS) to NO, which is a known inhibitor of SMC proliferation and collagen synthesis. Collectively, these arginase-driven events result in neointima formation, medial wall thickening, neovascularization of small arteries, vasoconstriction, and/or arterial stiffness.
Figure 3
Figure 3
Model for the regulation of atherosclerotic plaque progression and stability by arginase. The induction of arginase II activity in atherosclerosis stimulates plaque development and vulnerability by stimulating endothelial cell (EC) dysfunction, the inflammatory potential of macrophages, and arterial stiffness. In contrast, the induction of arginase I expression in atherosclerosis promotes plaque stability by blocking the inflammatory responses of macrophages and vascular smooth muscle cells (SMCs) and stimulating the proliferation of vascular SMCs.
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