Superoxide inhibition restores endothelium-dependent dilatation in aging arteries by enhancing impaired adherens junctions

Abstract

Endothelium-dependent, nitric oxide-mediated dilatation is impaired in aging arteries. The dysfunction reflects increased production of reactive oxygen species (ROS), is reversed by inhibiting superoxide with superoxide dismutase (SOD) mimics, and is assumed to reflect superoxide-mediated inactivation of nitric oxide. However, the dysfunction also reflects Src-dependent degradation and loss of vascular-endothelial (VE)-cadherin from adherens junctions, resulting in a selective impairment in the ability of the junctions to amplify endothelial dilatation. Experiments therefore tested the hypothesis that SOD mimics might restore endothelial dilation in aging arteries by inhibiting Src and protecting endothelial adherens junctions. Tail arteries from young and aging Fisher 344 rats were processed for functional (pressure myograph), biochemical (immunoblot), and morphological (immunofluorescence) analyses. Cell-permeable SOD mimics [manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP) or tempol] did not affect acetylcholine-induced dilatation in young arteries but increased responses and restored normal dilator function in aging arteries. In aging arteries, MnTMPyP decreased Src activity (immunoblots of Tyr phosphorylated compared with total Src), increased the intensity and width of VE-cadherin staining at endothelial junctions, and increased VE-cadherin levels in Triton X-100-insoluble lysates, which represents the junctional protein. Because of aging-induced junctional disruption, inhibiting VE-cadherin clustering at adherens junctions with a function-blocking antibody does not affect acetylcholine-induced dilatation in aging arteries. However, the antibody prevented SOD mimics from restoring acetylcholine-induced dilatation in aging arteries. Therefore, SOD mimics improve impaired adherens junctions in aging endothelium, which is essential for SOD mimics to restore endothelium-dependent dilatation in aging arteries. The results suggest an important new pathological role for ROS in aging endothelium, namely, disruption of adherens junctions. NEW & NOTEWORTHY Aging-induced endothelial dysfunction is reversed by SOD mimics. This study demonstrates that they improve impaired adherens junctions in aging endothelium and that their restoration of endothelial dilatation is dependent on increased junctional activity. The results suggest a novel role for oxygen radicals in vascular aging, namely, disruption of adherens junctions.

Silica nanomaterials induce organ injuries by Ca2+-ROS-initiated disruption of the endothelial barrier and triggering intravascular coagulation

“…Actin microfilaments can interact with endothelial adhesion structures and cooperatively regulate the cell shape. F-actin is a major actin protein in the endothelium and it is remodeled in response to nanomaterial exposure, oxidative stress and tumor necrosis factor [15,36,37]. Actin is an important component of "stress fibers" [38] and is responsible for endothelial contraction, which may lead to widening of inter-endothelial junctional gap and failure of the endothelial barrier [39].…”

Thrombin disrupts vascular endothelial‐cadherin and leads to hydrocephalus via protease‐activated receptors‐1 pathway

“…Previous studies suggested that thrombin increased the microvascular permeability by activating PAR1 pathway, which increased the activity of downstream protein kinases, such as p21‐activated kinase‐1 (PAK1) . Several lines of evidence also indicated that the phosphorylation of Src or PAK1 was involved in the degradation and loss of VE‐cadherin …”

“…19 Several lines of evidence also indicated that the phosphorylation of Src or PAK1 was involved in the degradation and loss of VE-cadherin. [22][23][24][25] In this study, we hypothesized that thrombin-induced hydrocephalus was related to the PAR1 signaling pathway which resulted in the decline of VE-cadherin in choroid plexuses. And this process may shed light on the formation of hydrocephalus after IVH.…”

Cellular cross-talks in the diseased and aging heart

“…In the aging heart, ECs shift the expression from laminin β2 to β1 and thereby modulate cell-matrix adhesion, cell migration and EndoMT in an autocrine manner that may impair vessel integrity [169]. Endothelial integrity is further disturbed by the age-related increase in ROS in the vasculature that leads to a Src-dependent degradation and loss of vascular-endothelial (VE)-cadherin from adherens junctions which impairs the ability to amplify endothelial dilation [170].…”

“…This pro-fibrotic and pro-inflammatory environment can be permissive for En-doMT and hence contribute to pathophysiologic alterations of the arterial wall like neointima formation and atherosclerosis. Evidences are given by studies showing that aged arterial ECs reduce internalization but increase degradation of VE-cadherin [170,179]. Furthermore, aging arterial ECs reveal a prominent intimal fibrous lesion with expression of rigid proteins such as collagen and fibronectin.…”