Shiseido discovers that a decrease in female hormone induces the dysfunction of lymphatic vessels in the skin

Shiseido discovered that female hormone contributes to the integrity of lymphatic vessels*1 in the skin, which are important for maintaining the skin homeostasis. Using its unique 3D technology*2 to visualize the internal structure of the skin, the abnormal morphology of lymphatic capillaries in the skin associated with the dysfunction was confirmed in post-menopausal women, who start to experience a rapid decline in female hormone. In addition, with the cooperation of Dr. Nobuyuki Takakura, Professor at Osaka University, apelin*3 was identified as a factor that induces the stabilization of lymphatic vessels by working synergistically with the decreasing female hormone as age progresses. Moreover, an extract of turmeric, a plant in the ginger family (Zingiberaceae), was found to enhance the weakened function of lymphatic vessels by promoting the production of apelin (Figure 1). We will continue to conduct advanced research from a holistic perspective to investigate the relationship between the skin and its internal conditions, such as blood vessels, lymphatic vessels, immunity, and nerves, and open up a new world of dermatological research. The results of the present study have been submitted in part to the Journal of Dermatological Science and were presented at the ISID (International Societies for Investigative Dermatology) meeting (2023/5/10-5/13) and the 47th Meeting of the Japanese Society of Lymphology (2023/6/9-6/10).
*1 Lymphatic vessels are present in peripheral tissues including the skin and serve as a starting point for the collection of waste products and excess water
*2 Shiseido Establishes Lymphatic Vessel Visualization Technology (2020) https://corp.shiseido.com/en/news/detail.html?n=00000000002997
*3 Apelin, a known component in living organisms, is a peptide composed of 13 or 36 amino acids
Shiseido Becomes the First to Reveal the Relationship between Impaired Lymphatic Function and “Sagging” Skin (2015)
https://corp.shiseido.com/jp/newsimg/archive/00000000001834/1834_a4z87_jp.pdf(Japanese)

Figure 1. Dysfunction of lymphatic vessels due to decreased female hormone and the effect of turmeric extract from the ginger family to promote functional recovery (conceptual diagram)

Figure 1

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Research background

Shiseido believes that the relationship with the inside of the body is important to bring out the natural beauty of the skin. We were among the first to tackle dermatological research from a holistic perspective based on the relationship with the whole body, including blood vessels, lymphatic vessel, immunity and nerves, and have applied this knowledge to our products.
Shiseido believes that the relationship with the inside of the body is important to bring out the natural beauty of the skin. We were among the first to tackle dermatological research from a holistic perspective based on the relationship with the whole body, including blood vessels, lymphatic vessel, immunity and nerves, and have applied this knowledge to our products. Lymphatic vessels are responsible for the removal of waste products in the body, and their involvement in ”swelling” of the body has been known. For many years, we have been conducting research with a focus on lymphatic vessels, which are important for maintaining skin homeostasis. So far, we have clarified how decreased function of lymphatic vessels leads to wrinkle formation and sagging*3,4, and elucidated the mechanism of lymphatic vessel aging as the fundamental cause of lymphatic dysfunction. Also, we have succeeded in three-dimensionally capturing the morphological changes when lymphatic vessel function was impaired*5,6. The present study was conducted with the aim of visually understanding how changes in the whole body affect the function of lymphatic vessels, and to this end, the relationship between female hormone and lymphatic vessels was investigated.
*4 Shiseido clarifies that impaired lymphatic vessel function is a cause of wrinkle formation
https://corp.shiseido.com/jp/newsimg/archive/00000000000905/905_a5c92_jp.pdf（Japanese）
*5 Shiseido Reaches World’s First Elucidation of Aging Mechanism of Lymphatic Vessels in the Skin (2020)
https://corp.shiseido.com/en/news/detail.html?n=00000000002998
*6 Shiseido Succeeds in 3D Visualization of Morphological Changes in Dysfunctional Lymphatic Capillaries (2023)
https://corp.shiseido.com/en/news/detail.html?n=00000000003620

Morphological changes of lymphatic capillaries in the skin associated with menopause

It has previously been known that the lymphatic flow becomes restricted in post-menopausal women, when female hormone rapidly decreases, making women more prone to swelling. However, their mechanism has not been clarified. In the present study, the skin of women in each age group was analyzed using 3D visualization technology in order to assess the morphological changes of lymphatic capillaries in pre- and post-menopause. As a result, the volume of lymphatic capillaries was reduced in post-menopause, and that the vessels have become thin and fragile. These findings suggest that a decrease in female hormone may be one of the causes of functional impairment of lymphatic vessels in the skin, with the resulting morphological changes (Figure 2).

Figure 2. Lymphatic function is impaired due to decreased female hormone

Figure 2

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Apelin works synergistically with female hormone to contribute to the stabilization of lymphatic vessels

Female hormone induce cell proliferation and stabilization through its receptor expressed in lymphatic endothelial cells (Figure 3). Thus, considering the age-related decrease in the secretion of female hormone that has a protective effect on the function of lymphatic vessels, we explored factors that work synergistically with low concentrations of female hormone and enhance their effect. With the cooperation of Dr. Takakura, we identified apelin, which is a well-known factor that stabilizes the vascular integrity, to possess this ability.
The function of apelin on lymphatic vessels has already been clarified in our previous study, and this time, we examined how apelin can assist in the actions of female hormone that are reduced in post-menopause. We found that the cell-cell adhesion was stronger when they were stimulated simultaneously with both apelin and female hormone than individual stimulation with each factor (Figure 4). These results revealed that apelin works synergistically with female hormone to induce stabilization of lymphatic vessels.

Figure 3. Female hormone promotes the proliferation of lymphatic endothelial cells
Figure 4. Co-stimulation of apelin and female hormone strengthen the cell-cell adhesion

Figure 3

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Figure 4

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The turmeric extract from the ginger family promotes the production of apelin and stabilizes lymphatic vessels

A search for active ingredients that can promote the production of apelin, which works synergistically with female hormone, led to the discovery of an ”turmeric extract from the ginger family.” We confirmed the effect of this extract to strengthen cell-cell adhesion in lymphatic vessels and thereby stabilize lymphatic vessels by promoting the production of apelin (Figure 5).

Future prospects
In the present study, we clarified that changes in female hormone, which are important for maintaining the homeostasis of the whole body, affect the function of lymphatic vessels in the skin, and found the possibility that the impaired function of lymphatic capillaries could lead to skin problems such as wrinkles and sagging that increasingly occur in post-menopause. Accordingly, by clarifying the relationship between the whole body and lymphatic vessels, which are responsible for the removal of waste products, we will demonstrate the importance of maintaining the function of lymphatic vessel in producing healthy skin. Shiseido aims to bring out the original beauty of each and every person by challenging beauty innovation that works not only on the surface of the skin but also inside and outside of the skin, moving toward the realization of the company's management strategy vision, ”Personal Beauty Wellness Company.”
About Our R＆D Strategy:
Under ”Skin Beauty INNOVATION,” one of the three pillars of the company's R＆D strategy, the present study was carried out in the field of ”skin foundation,” which aims to elucidate the relationships between the skin and the conditions inside the skin, such as blood vessels and lymphatic vessels, immunity, and nerves.
- Integrated Report 2022 (Beauty Innovation)
https://corp.shiseido.com/report/en/2022/value_creation/innovation/
- Keywords
Skin Beauty INNOVATION, skin foundation, lymphatic vessels

Figure 5: Turmeric extract from the ginger family stabilizes lymphatic vessels by increasing apelin gene expression

Figure 5

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