Abstract
Arterial stiffness, which increases with aging and hypertension, is an independent cardiovascular risk factor. While stiffer substrates are known to affect single endothelial cell morphology and migration, the effect of substrate stiffness on endothelial monolayer function is less understood. The objective of this study was to determine if substrate stiffness increased endothelial monolayer reactive oxygen species (ROS) in response to protein kinase C (PKC) activation and if this oxidative stress then impacted adherens junction integrity. Porcine aortic endothelial cells were cultured on varied stiffness polyacrylamide gels and treated with phorbol 12-myristate 13-acetate (PMA), which stimulates PKC and ROS without increasing actinomyosin contractility. PMA-treated endothelial cells on stiffer substrates increased ROS and adherens junction loss without increased contractility. ROS scavengers abrogated PMA effects on cell-cell junctions, with a more profound effect in cells on stiffer substrates. Finally, endothelial cells in aortae from elastin haploinsufficient mice (Eln+/-), which were stiffer than aortae from wild-type mice, showed decreased VE-cadherin colocalization with peripheral actin following PMA treatment. These data suggest that oxidative stress may be enhanced in endothelial cells in stiffer vessels, which could contribute to the association between arterial stiffness and cardiovascular disease.
Highlights
Due to the highly mechanical nature of the cardiovascular system, cardiovascular disease has long been accepted as both a biomechanical and biochemical disease
We show that substrate stiffness enhances phorbol 12-myristate 13-acetate (PMA)-induced oxidative stress in endothelial monolayers in vitro and alters actin fiber reorganization and adherens junction morphology both in vitro and ex vivo
Aortic stiffness had not been characterized by atomic force microscopy in this mouse model
Summary
Due to the highly mechanical nature of the cardiovascular system, cardiovascular disease has long been accepted as both a biomechanical and biochemical disease. Arterial stiffness, which increases with hypertension and aging among others, is an independent predictor of cardiovascular risk [1,2,3]. Stiff arteries have long been known to contribute to cardiovascular mortality by increasing cardiac afterload [10]; more recently, stiff arteries have been shown to contribute to endothelial dysfunction, an initiating step in atherosclerosis [11,12,13]. Endothelial permeability was elevated in stiffened aortae from older mice [12]. Mesenteric arteries from elastin haploinsufficient (Eln+/-) mice had enhanced angiotensin-induced vasoconstriction and impaired endothelium-dependent vasodilation [13], aortae from these same animals do not [16]. Arterial stiffness alone may contribute to cardiovascular risk by altering critical endothelial functions
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