Inward remodeling of resistance arteries requires reactive oxygen species-dependent activation of matrix metalloproteinases

Abstract

Inward eutrophic remodeling is the most prevalent structural change of resistance arteries in hypertension. Sympathetic and angiotensin (ANG)-induced vasoconstriction has been associated with hypertension and with the production of matrix metalloproteinases (MMPs) and ROS. Therefore, we hypothesize that prolonged exposure to norepinephrine (NE) and ANG II induces arteriolar inward remodeling dependent on the activation of MMPs and the production of ROS. This hypothesis was tested on rat cremaster arterioles that were isolated, cannulated, pressurized, and exposed to either NE (10(-5.5) mol/l) + ANG II (10(-7) mol/l) or vehicle (control) for 4 h. The prolonged exposure to NE + ANG II induced inward remodeling, as evidenced by the reduced maximal arteriolar passive diameter observed after versus before exposure to the vasoconstrictor agonists. NE + ANG II also increased the arteriolar expression and activity of MMP-2 and the production of ROS as determined, respectively, by real-time RT-PCR, gel and in situ zymography, and the use of ROS-sensitive dyes with multiphoton microscopy. Inhibition of MMP activation (with GM-6001) or ROS production (with apocynin or tempol) prevented the NE + ANG II-induced inward remodeling. Inhibition of ROS production prevented the activation of MMPs and the remodeling process, whereas inhibition of MMP activation did not affect ROS production. These results indicate that prolonged stimulation of resistance arterioles with NE + ANG II induces a ROS-dependent activation of MMPs necessary for the development of arteriolar inward remodeling. These mechanisms may contribute to the structural narrowing of resistance vessels in hypertension.

Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization

“…Thus far, our results indicate remodeling occurs in response to 5-HT, and not in response to NE ϩ Ang II. We used NE ϩ Ang II because we have previously shown that a 4-h incubation in this combination of vasoconstrictors consistently induces inward remodeling in isolated arterioles (32,45). Topical application of this combination of vasoconstrictors in vivo was unable to maintain arteriolar constriction over the duration of the experiment, even when supplemented with L-NAME or indomethacin.…”

“…In isolated vessels ex vivo, it has been demonstrated that prolonged (4 hϩ) exposure of resistance arteries to vasoconstrictors initiates the inward remodeling process via pathways that include both the polymerization of actin and the activation of transglutaminases, specifically transglutaminase 2 (5,32,45). In vivo studies investigating the role of the actin cytoskeleton on inward remodeling within the resistance vasculature are limited.…”

Metabolic syndrome impairs reactivity and wall mechanics of cerebral resistance arteries in obese Zucker rats

“…Not only does a prooxidative stress [reactive oxygen species (ROS)] environment impact the NO pathway and its regulation of arterial remodeling, but ROS can independently interact with the components of the perivascular matrix and drive collagen cross-linking, collagen deposition, and the fracturing of elastin (8). Previous evidence suggests that eutrophic inward remodeling was dependent on ROS activation of specific matrix metalloproteinases (that degrade and reorganize the extracellular matrix of the vessel wall) (36). Importantly, tempol was highly effective at lowering nitrotyrosine, TNF-␣, and monocyte chemotactic protein-1 concentrations in the OZR (Table 1), in addition to improving arterial reactivity, reducing stiffness, and restoring NO bioavailability.…”

Matrix Metalloproteinase 2 as a Potential Mediator of Vascular Smooth Muscle Cell Migration and Chronic Vascular Remodeling in Hypertension

“…On the other hand, it was found that inhibition of MMPs with GM6001 or reducing RONS levels with tempol prevented the norepinephrine- and angiotensin II-induced inward remodeling of rat cremaster arterioles. Interestingly, RONS inhibition reduced the arteriolar activity of MMP-2, whereas MMP inhibition did not affect RONS production, indicating that RONS are upstream of MMP activation during inward remodeling [58]. Inhibition of MMP and transforming growth factor (TGF)-β signaling also prevented warfarin-induced elastocalcinosis, elastin proteolysis, arterial stiffness and hypertension in rats [59].…”