Cyclic Stretch, Reactive Oxygen Species, and Vascular Remodeling

Abstract

Blood vessels respond to changes in mechanical load from circulating blood in the form of shear stress and mechanical strain as the result of heart propulsions by changes in intracellular signaling leading to changes in vascular tone, production of vasoactive molecules, and changes in vascular permeability, gene regulation, and vascular remodeling. In addition to hemodynamic forces, microvasculature in the lung is also exposed to stretch resulting from respiratory cycles during autonomous breathing or mechanical ventilation. Among various cell signaling pathways induced by mechanical forces and reported to date, a role of reactive oxygen species (ROS) produced by vascular cells receives increasing attention. ROS play an essential role in signal transduction and physiologic regulation of vascular function. However, in the settings of chronic hypertension, inflammation, or acute injury, ROS may trigger signaling events that further exacerbate smooth muscle hypercontractility and vascular remodeling associated with hypertension and endothelial barrier dysfunction associated with acute lung injury and pulmonary edema. These conditions are also characterized by altered patterns of mechanical stimulation experienced by vasculature. This review will discuss signaling pathways regulated by ROS and mechanical stretch in the pulmonary and systemic vasculature and will summarize functional interactions between cyclic stretch-and ROS-induced signaling in mechanochemical regulation of vascular structure and function.

Macrophage Migration Inhibitory Factor: A Novel Inhibitor of Apoptosis Signal-Regulating Kinase 1–p38–Xanthine Oxidoreductase–Dependent Cigarette Smoke–Induced Apoptosis

“…Important vascular sources of ROS are XOR, uncoupled nitric oxide synthase, and nicotinamide adenine dinucleotide phosphate oxidase (22)(23)(24). More specifically, XOR is a source of superoxide and hydrogen peroxide within pulmonary EndoCs.…”

Nitric oxide synthase 3 contributes to ventilator-induced lung injury

“…NOS3 uncoupling, ROS production, and endothelial dysfunction can be prevented by administration of BH 4 and ascorbic acid (22,27). It is known that ROS can disrupt the endothelial barrier and induce inflammation (8,9,16,40). The role of ROS in the pathogenesis of VILI is generally accepted (8, 29), but the sources of ROS have not been fully defined.…”

“…Under certain conditions, such as substrate (L-arginine) or cofactor (e.g., tetrahydrobiopterin, BH 4 ) depletion, NOS3 catalyzes the "uncoupled" reduction of O 2 and produces superoxide (13). Under conditions of increased oxidative stress, such as those known to develop in VILI (8,29), BH 4 levels may decline leading to NOS3 uncoupling (22,23,26). ROS production by uncoupled NOS3 contributes to endothelial dysfunction observed in hypertension, hyperglycemia, and hypercholesterolemia (3,13,23,24).…”

Live Cell Imaging during Mechanical Stretch

“…Reactive oxygen species include molecules and free radicals derived from molecular oxygen with high reactivity to lipids, proteins, polysaccharides, and nucleic acids [22][23][24] . ROS serve as a common intracellular signal to regulate ion channel function, protein kinase/ phosphatase activation, and gene expression, but excessive or unregulated production can contribute to apoptotic and necrotic cell death, neurodegeneration, atherosclerosis, diabetes, and cancer 24,25 .…”