Matrix Metalloproteinases and Arterial Hypertension: Role of Oxidative Stress and Nitric Oxide in Vascular Functional and Structural Alterations

Abstract

Various pathophysiological mechanisms have been implicated in hypertension, but those resulting in vascular dysfunction and remodeling are critical and may help to identify critical pharmacological targets. This mini-review article focuses on central mechanisms contributing to the vascular dysfunction and remodeling of hypertension, increased oxidative stress and impaired nitric oxide (NO) bioavailability, which enhance vascular matrix metalloproteinase (MMP) activity. The relationship between NO, MMP and oxidative stress culminating in the vascular alterations of hypertension is examined. While the alterations of hypertension are not fully attributable to these pathophysiological mechanisms, there is strong evidence that such mechanisms play critical roles in increasing vascular MMP expression and activity, thus resulting in abnormal degradation of extracellular matrix components, receptors, peptides, and intracellular proteins involved in the regulation of vascular function and structure. Imbalanced vascular MMP activity promotes vasoconstriction and impairs vasodilation, stimulating vascular smooth muscle cells (VSMC) to switch from contractile to synthetic phenotypes, thus facilitating cell growth or migration, which is associated with the deposition of extracellular matrix components. Finally, the protective effects of MMP inhibitors, antioxidants and drugs that enhance vascular NO activity are briefly discussed. Newly emerging therapies that address these essential mechanisms may offer significant advantages to prevent vascular remodeling in hypertensive patients.

Keywords: EGFR; NADPH oxidase; angiotensin II; endothelial dysfunction; fibrosis; phenylephrine; vascular remodeling; vasoconstriction.

Figure 1

MMP inhibition and interaction between MMPs and reactive oxygen species (ROS). Increased levels of superoxide (O₂⁻), hydrogen peroxide (H₂O₂) and peroxynitrite (ONOO⁻) can activate matrix metalloproteinases (MMPs) [6,7,8]. MMP-2 and MMP-7 activate pro-oxidant pathways in the vascular tissue via epidermal growth factor receptor (EGFR) transactivation [12,69]. ROS can also lead to the formation of a truncated MMP-2 (NTT-MMP-2) with 65 kDa located in the mitochondria and cytosol, which downregulates genes associated with resistance to oxidative stress [67]. High ROS concentrations may decrease MMP activity [7,8].

Figure 2

MMPs induce vasoconstriction and vascular dysfunction through different mechanisms. Phenylephrine (PE), angiotensin II (Ang-II), and endothelin-1 (ET-1) mediate vasoconstriction by generating reactive oxygen species (ROS); this mechanism is essential to maintain vasoconstriction. MMP-2 and MMP-7 are required for Ang-II and PE to induce vasoconstriction by transactivation of the epidermal growth factor receptor (EGFR) [12,69]. MMP-2 also induces vasoconstriction by cleaving big endothelin-1 (Big ET-1) to endothelin 1–32 (ET 1–32) [14]. The action of MMP-2 on adrenomedullin leads to the formation of metabolites with vasoconstrictive activity [78]. MMPs (not identified yet) cleave the beta-2 adrenergic receptor, contributing to increased arteriolar tone in spontaneously hypertensive rats [30]. MMP-9 can increase the vasoconstriction of arterioles and venules by a mechanism not yet clarified [30]. These processes may contribute to hypertension.

Figure 3

MMPs induce endothelial dysfunction by different mechanisms. MMP-2 and MMP-7 are required for phenylephrine (PE) to induce reactive oxygen species (ROS) by transactivation of the epidermal growth factor receptor (EGFR) [12,69]. MMP-2 is also required for angiotensin II (Ang-II) to increase perivascular ROS formation [32]. MMP-2 cleaves the vasodilator peptide related to the calcitonin gene (CGRP) into peptides with more minor vasodilatory effects, and MMP-9 decreases endothelial nitric oxide synthase (eNOS) expression and vasodilatation in resistance arteries [80]. ROS decrease endothelium-derived relaxing factors’ (EDRFs’) bioavailability, such as NO, leading to endothelial dysfunction and hypertension.

Figure 4

Oxidative stress inhibition reduces MMP activation in hypertension. Uncoupled eNOS and MMPs produce superoxide (O₂⁻) that uses NO for peroxynitrite (ONOO⁻) production causing MMP activation and consequently vascular remodeling and dysfunction. Thus, MMP inhibitors and drugs with antioxidant properties can inhibit MMP activation, improving vascular function and reverting vascular remodeling. Doxycycline has antioxidant effects but also relies on direct inhibition of the active forms of MMPs. Drugs capable of augmenting NO bioavailability are also related to MMP inhibition, but further studies are needed to establish the relation between augmentation in NO (and NO-related species) and MMPs in hypertension.