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.

FIG. 1.

Metabolism of reactive oxygen species.

FIG. 2.

Metabolic and enzymatic sources of ROS. NOS, nitric oxide synthase; ROS, reactive oxygen species; XOR, xanthine oxidase.

FIG. 3.

Regulation of vascular structure and function by ROS.

FIG. 4.

Major signaling pathways and cellular responses induced by cyclic stretch.

FIG. 5.

Mechanisms of stretch-induced ROS production.

FIG. 6.

Role of ROS in cyclic stretch-induced vascular remodeling and endothelial activation.

FIG. 7.

Synergistic effect of high magnitude cyclic stretch and VEGF on ROS production by pulmonary endothelial cells. Static controls or cells preconditioned at 18% CS were exposed to vehicle or VEGF (200 ng/ml, 15 min), and ROS production was measured using EC preincubation with fluorescent ROS sensor DCFDA followed by fluorimetric analysis. Shown are mean ± SD of three independent experiments, *p < 0.05.

FIG. 8.

Role of ROS in pulmonary endothelial barrier disruption induced by high magnitude cyclic stretch and VEGF. EC were left static or exposed to cyclic stretch at 18% linear elongation for 2 h, followed by stimulation with VEGF (200 ng/ml, 15 min). (A) Immunoflourescence staining of F-actin was performed using Texas Red conjugated phalloidin. Arrows indicate cyclic stretch- and VEGF-induced paracellular gap formation. (B) Quantitative image analysis of gap formation induced by 18% CS and VEGF. Shown are mean ± SD of four independent experiments, *p < 0.05.

FIG. 9.

Attenuation of pulmonary endothelial barrier disruption induced by high magnitude cyclic stretch and VEGF by ROS scavenger N-acetyl cysteine. EC exposed to 18% CS were pretreated with NAC (1 mM, 30 min) prior to VEGF stimulation (200 ng/ml, 15 min). (A) Immunoflourescence staining of F-actin was performed using Texas Red conjugated phalloidin. Arrows indicate cyclic stretch- and VEGF-induced paracellular gap formation. (B) Quantitative analysis of gap formation induced by 18% CS and VEGF in untreated and NAC-pretreated cells. Shown are mean ± SD of three independent experiments, *p < 0.05.