Magnolol inhibits venous remodeling in mice

Abstract

Due to gravity the venous vasculature in the lower extremities is exposed to elevated pressure levels which may be amplified by obesity or pregnancy. As a consequence, venules dilate and may be slowly transformed into varicose or spider veins. In fact, chronically elevated venous pressure was sufficient to cause the corkscrew-like enlargement of superficial veins in mice. We hypothesized that biomechanical activation of endothelial cells contributes to this process and investigated the inhibitory capacity of Magnolol in this context – a natural compound that features multiple properties counteracting cellular stress. While Magnolol did not influence endothelial capillary sprout formation, it interfered with proliferation, ERK1/2 activity, gelatinase activity as well as baseline production of reactive oxygen species in these cells or murine veins. The anti-oxidative and anti-proliferative capacity of Magnolol was mediated through stimulation of heme oxygenase-1 expression. Finally, local transdermal application of Magnolol attenuated pressure-mediated development of varicose/spider veins in mice and was accompanied by the absence of proliferating and MMP-2 positive endothelial cells. Collectively, our data identified Magnolol as a potent inhibitor of biomechanically evoked endothelial cell activity during pressure-mediated venous remodeling processes which contribute to the development of varicose and spider veins.

Glycyrrhetinic Acid Antagonizes Pressure-Induced Venous Remodeling in Mice

“…Indeed, risk factors causing increased pressure in the abdomen (e.g., obesity, pregnancy) may initiate and promote venous remodeling (Sisto et al, 1995 ; Pfisterer et al, 2014a ). In line with this idea, an increase in venous filling pressure alone supports enlargement and dilatation of superficial veins in mice (North and Sanders, 1958 ; Feldner et al, 2011 ; Kuk et al, 2017 ). In humans, pressure/wall stress-induced remodeling of superficial veins may in fact be explained by direct connection to the deep venous plexus as was evidenced by the increase in perfusion of a spider vein upon muscle contraction-mediated pressure increase in the deep veins.…”

“…Despite the ambivalent effects of GA observed so far, it robustly inhibited the capacity of both human and mouse ECs and SMCs to degrade gelatin-based matrices. This inhibitory feature may in fact attenuate the renovation of the extracellular matrix in the context of venous remodeling which is usually associated with increased activity of matrix metalloproteinases (MMP-2/9) in animal models (Pascarella et al, 2005 ; Raffetto et al, 2008 ; Eschrich et al, 2016 ; Kuk et al, 2017 ) and diseased human veins (Woodside et al, 2003 ; Kowalewski et al, 2004 ; Nomura et al, 2005 ). As our findings did not reveal a GA-mediated down-regulation of the MMP2/9 expression, its observed gelatinase-inhibiting effect may be based on its direct interference with the enzymatic activity as has been described for many other enzymes such as 11beta-hydroxysteroid dehydrogenase (Monder et al, 1989 ), tyrosinase (Um et al, 2003 ), hyaluronidase (Hertel et al, 2006 ).…”

“…As normality tests of small samples (<10) have little power to discriminate between Gaussian and non-gaussian populations, we made assumptions about their distribution in a given basic population by considering the variability/scatter/source of scatter of data from previous experiments assessing the same variables(Feldner et al, 2011 ; Eschrich et al, 2016 ; Kuk et al, 2017 ). For the presented experimental data, we expect a Gaussian distribution.…”

“…A number of risk factors have been associated with the development of spider veins, including prolonged sitting or standing, pregnancy, being overweight, wearing tight undergarments or clothes which suggest an underlying increase in the hydrostatic venous filling pressure associated with the deep veins in the lower extremities (Sisto et al, 1995 ; Pfisterer et al, 2014a ). 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 ). In fact, 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 ).…”

Insights on the Multifunctional Activities of Magnolol

“…The possible underlying mechanism might be associated with the antiproliferative and antioxidative activity of magnolol through enhancement of HO-1 signaling and downregulation of cell proliferation, ERK1/2 activity, gelatinase activity, and ROS baseline production. However, the formation of endothelial capillary sprout is not influenced by magnolol [111]. In concanavalin A (ConA)-stimulated transformation from CD4+ T cells to CD4+T helper (Th17) cells in liver, magnolol significantly inhibits this cellular polarization, Th17 cell differentiation, and IL-17A production.…”