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

Figures

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  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].

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  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.

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  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.

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  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.