The role of caveolae in endothelial cell dysfunction with a focus on nutrition and environmental toxicants

Abstract

Complications of vascular diseases, including atherosclerosis, are the number one cause of death in Western societies. Dysfunction of endothelial cells is a critical underlying cause of the pathology of atherosclerosis. Lipid rafts, and especially caveolae, are enriched in endothelial cells, and down-regulation of the caveolin-1 gene may provide protection against the development of atherosclerosis. There is substantial evidence that exposure to environmental pollution is linked to cardiovascular mortality, and that persistent organic pollutants can markedly contribute to endothelial cell dysfunction and an increase in vascular inflammation. Nutrition can modulate the toxicity of environmental pollutants, and evidence suggests that these affect health and disease outcome associated with chemical insults. Because caveolae can provide a regulatory platform for pro-inflammatory signalling associated with vascular diseases such as atherosclerosis, we suggest a link between atherogenic risk and functional changes of caveolae by environmental factors such as dietary lipids and organic pollutants. For example, we have evidence that endothelial caveolae play a role in uptake of persistent organic pollutants, an event associated with subsequent production of inflammatory mediators. Functional properties of caveolae can be modulated by nutrition, such as dietary lipids (e.g. fatty acids) and plant-derived polyphenols (e.g. flavonoids), which change activation of caveolae-associated signalling proteins. The following review will focus on caveolae providing a platform for pro-inflammatory signalling, and the role of caveolae in endothelial cell functional changes associated with environmental mediators such as nutrients and toxicants, which are known to modulate the pathology of vascular diseases.

Oleic acid increases mitochondrial reactive oxygen species production and decreases endothelial nitric oxide synthase activity in cultured endothelial cells

“…The high levels of reactive oxygen species production induced by OA may account for the impaired insulin-induced eNOS activity. Possibly, incorporation of OA-enriched phospholipid into the cell membrane affects the conformation of caveolae (Majkova et al, 2010). Many receptors are localized in caveolae of endothelial cells, including the insulin receptor (Wary et al, 1998) and other receptors (Patel et al, 2008) involved in eNOS signaling, as well as eNOS itself (Govers et al, 2002).…”

Epigallocatechin-gallate stimulates NF-E2-related factor and heme oxygenase-1 via caveolin-1 displacement

“…In line with these functional characteristics, caveolae can provide a regulatory platform for proinflammatory signaling associated with vascular diseases such as atherosclerosis [30]. For example, enriching endothelial cells with docosahexaenoic acid can affect caveolae-associated nitric oxide synthase activity [31], a process which may be linked to caveolae-mediated endocytosis [32].…”

Treatment with n-3 polyunsaturated fatty acids reverses endothelial dysfunction and oxidative stress in experimental menopause

“…Potential mechanisms underlying beneficial effects of n-3 PUFA on endothelial dysfunction and atherosclerosis include enhanced vasodilation by correction of the imbalance between vasoconstrictor and vasodilator endothelium-derived factors [11], inhibition of nuclear factor kappa B (NF-kB) activation and of cyclooxygenase-2 (COX-2) expression [11], reduction of endothelial expression of adhesion molecules [12,13], suppression of leukocyte adhesion to endothelial cells [14] and modulation of oxidative stress [15][16][17]. Several studies suggest a link between n-3 PUFA-mediated cardioprotective effects and the involvement of caveolae [18], a subset of membrane lipid rafts which plays a key role in endothelial function [19]. By modulating caveolar lipid composition, dietary fatty acids ultimately regulate caveolar signal transduction pathway responses [20].…”