Abstract
Development of spider veins is caused by the remodeling of veins located in the upper dermis and promoted by risk factors such as obesity or pregnancy that chronically increase venous pressure. We have repeatedly shown that the pressure-induced increase in biomechanical wall stress is sufficient to evoke the formation of enlarged corkscrew-like superficial veins in mice. Subsequent experimental approaches revealed that interference with endothelial- and/or smooth muscle cell (SMC) activation counteracts this remodeling process. Here, we investigate whether the herbal agent glycyrrhetinic acid (GA) is a suitable candidate for that purpose given its anti-proliferative as well as anti-oxidative properties. While basic abilities of cultured venous SMCs such as migration and proliferation were not influenced by GA, it inhibited proliferation but not angiogenic sprouting of human venous endothelial cells (ECs). Further analyses of biomechanically stimulated ECs revealed that GA inhibits the DNA binding capacity of the mechanosensitive transcription factor activator protein-1 (AP-1) which, however, had only a minor impact on the endothelial transcriptome. Nevertheless, by decreasing gelatinase activity in ECs or mouse veins exposed to biomechanical stress, GA diminished a crucial cellular response in the context of venous remodeling. In line with the observed inhibitory effects, local transdermal application of GA attenuated pressure-mediated enlargement of veins in the mouse auricle. In summary, our data identifies GA as an inhibitor of EC proliferation, gelatinase activity and venous remodeling. It may thus have the capacity to attenuate spider vein formation and remodeling in humans.
Highlights
Pathologic remodeling of veins often results in significant morbidity and discomfort for the patient while remodeling of smaller, i.e., superficial veins results in formation of spider veins or telangiectasias that often cause a cosmetic nuisance/discontent
Sprouting assays revealed that glycyrrhetinic acid (GA) did not interfere with the migratory capacity of endothelial cells (ECs) and smooth muscle (SMC) (Figures 2C,D)
The initiating triggers for venous remodeling processes associated with spider-vein formation in particular have been a subject of debate
Summary
Pathologic remodeling of veins often results in significant morbidity and discomfort for the patient while remodeling of smaller, i.e., superficial veins results in formation of spider veins or telangiectasias that often cause a cosmetic nuisance/discontent. While details of the pathophysiology of spider veins are still unknown, former work of our group revealed that chronic elevation of the venous pressure is sufficient to drive venous remodeling in mice (Feldner et al, 2011; Pfisterer et al, 2014a; Kuk et al, 2017). Some reports hypothesize that telangiectasias may arise from varicose veins of larger vessels due to venous hypertension caused by valvular damage resulting in reflux and venous dilatation (Thomson, 2016). With reference to the law of Laplace, elevated pressure levels result in an increase in wall stress or biomechanical (over)load of the venous vessel wall within the affected venous network to drive its further remodeling (Partsch, 2009; Atta, 2012). Counteracting mechanisms which are rate limiting for this process such as activation of the mechanoresponsive transcription factor activator protein 1 (AP1) or cellular proliferation have been shown to interfere with venous remodeling (Feldner et al, 2011; Pfisterer et al, 2014b)
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