Age-related structural alterations of skeletal muscles and associated capillaries.

Aging is associated with a progressive decline in muscle mass, strength, and quality. We have previously demonstrated the important role of the blood vasculature system in ultraviolet (UV) light-induced changes in skin and its molecular mechanisms. Whereas recent findings revealed structural alterations of the cutaneous vasculature in aged and photoaged human skin, structural changes of blood vessels in skeletal muscles with age have remained unclear. Although, facial skeletal muscles could be involved in skin-aging, here, we show-for the first time-that, in the lateral great muscle, the cross-sectional muscle fiber area and vessels size were decreased in older skin compared with that in younger skin. In the orbicularis oculi muscle, no significant interaction between age and the muscle fiber area was observed. However, a significantly decreased ratio of muscle area was indicated in older skin compared with that in younger skin. Interestingly, the pericyte-covered vessels ratio was decreased in older skin. Therefore, we found that the skeletal muscle capillary destabilizes with age. In summary, we revealed that the lateral great muscle and the orbicularis oculi muscle fibers become thinner with age due to the destabilization of skeletal muscle capillaries. Therapeutic targeting of muscle capillaries might affect the decline of skeletal muscles with age and could potentially regulate muscle/skin-aging.

Antiedema effects of Siberian ginseng in humans and its molecular mechanism of lymphatic vascular function in vitro.

The lymphatic system in the skin plays a major role in tissue fluid homeostasis, in the afferent phase of the immune response, and in tumor metastasis. Although lymphangiogenic factors involved in embryonic development and the metastatic spread of tumor cells have been well studied, little is known about small-molecule compounds that activate lymphatic function, especially under physiological conditions. We hypothesized that the identification of a lymphatic-activating compound could provide a method for improving edema. Here, we show that Siberian ginseng (Eleutherococcus senticosus) and its component eleutheroside E induce phosphorylation of the endothelial-specific receptor Tie2 in vitro. The activation of Tie2 on lymphatic endothelial cells (LECs) is known to stabilize lymphatic vessels, so we examined the effects of Siberian ginseng on LECs. We found that Siberian ginseng induces the migration and cord formation of LECs. Permeability assays demonstrated that it stabilizes LECs by promoting the intercellular localization of vascular endothelial cadherin, which is an endothelium-specific cell-cell adhesion molecule involved in endothelial barrier function, and it induces the phosphorylation of endothelial nitric oxide synthase by LECs. These effects appear to be mediated by the activation of Tie2 in LECs. Finally, we investigated whether the consumption of Siberian ginseng powder improves edema in a 2-way, randomized, crossover study in 50 healthy female volunteers. Edema of the lower limbs was significantly attenuated at 2 and 4hours after ingestion as compared with the control group. Thus, we demonstrate that Siberian ginseng exerts its potent antiedema activity mainly by promoting lymphatic function.

Electric current-induced lymphatic activation.

The lymphatic system in skin plays important roles in drainage of wastes and in the afferent phase of immune response. We previously showed that activation of vascular endothelial growth factor receptor (VEGFR), specifically the VEGFC/VEGFR-3 pathway, attenuates oedema and inflammation by promoting lymphangiogenesis, suggesting a protective role of lymphatic vessels against skin inflammation. However, it remains unknown how physical stimuli promote lymphatic function. Here, we show that lymphatic endothelial cells (LECs) are activated by direct-current (DC) electrical stimulation, which induced extension of actin filaments of LECs, increased calcium influx into LECs, and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK). An inhibitor of focal adhesion kinase, which plays a role in cellular adhesion and motility, diminished the DC-induced extension of F-actin and abrogated p38 phosphorylation. Time-lapse imaging revealed that pulsed-DC stimulation promoted proliferation and migration of LECs. Overall, these results indicate that electro-stimulation activates lymphatic function by activating p38 MAPK.