Vascular Medicine

Members

Theme Leader :
Masashi Toyoda, Ph.D.
Researcher: Norihiko Sasaki, Ph.D., Yoko Itakura, Ph.D.
External Researcher: Kazuhiro Shigemoto, M.D., Ph.D.
Research students: 3

Keywords

Cardiovascular System, Glycan, Aging and Senescence, Microvascular Regulation, Permeability, Arteriosclerosis, Heart-Kidney Connection, Functional Regeneration, Stem Cells

Major Research Titles

1. The Maintenance of Cardiac Tissue Function and Aging-Related Changes
2. The Mechanisms of Age-Related Disease Onset Through Vascular and Vascular-Mediated Inter-Organ Interactions
3. Cardiac Tissue Regeneration and Its Underlying Mechanisms

Profile

With the aging population and recent outbreaks of respiratory infections, a "heart failure and respiratory failure pandemic" is predicted, where the number of patients with heart failure and respiratory failure will increase sharply. While treatments for cardiovascular diseases improve daily, ongoing basic research is essential to address these future concerns.
We conduct basic research aimed at understanding the mechanisms behind age-related diseases that affect the cardiovascular system and creating preventive strategies.
The heart keeps beating throughout a person's entire life, supplying oxygen and nutrients to the whole body through an extensive network of blood vessels, making it vital for sustaining life. In reality, the decline in cardiovascular function with age often shows as a range of subjective symptoms like headaches, palpitations, fatigue, and chest pain, which can lead to decreased physical activity. This frequently affects mental well-being and results in a significant drop in quality of life (QOL). However, distinguishing whether these subjective symptoms are "natural occurrences" of aging or "signs indicating serious disease" can be surprisingly difficult. Sometimes, this uncertainty delays diagnosis, allowing conditions to worsen. Our goal is to detect "small changes within tissues" that likely happen long before tissue function declines and causes significant impairment. We are also conducting research to regenerate lost function.
We are conducting our research with the hope that its results will not only enable faster diagnosis and treatment in the future but also help prevent the development of cardiovascular disease.

Recent Publications:
1) Nakamura M, Yoshida-Kikkawa Y, Sugiura K, Itakura Y, Ohse K, Sasaki N, Ito Y, Toyoda M. Assessment of permeability in deep tissue capillaries using a new method reflects the nutrient supply status in a healthy heart. Regen Ther 30:900-909, 2025.
DOI: https://doi.org/10.1016/j.reth.2025.10.005
Erratum: Regen Ther 30:1067-1068, 2025.
DOI: https://doi.org/10.1016/j.reth.2025.11.001

2) Sasaki N, Kawakami K, Itakura Y, Fujita T, Miyagawa S, Ishigami T, Kubo H, Miura Y, Chiba Y. Characterization of extracellular vesicles derived from cortical bone stem cells compared with mesenchymal stem cells. Mol Cell Biochem 480(11):5861-5876, 2025.
DOI: https://doi.org/10.1007/s11010-025-05348-2

3) Ding Y, Kowada T, Matsui T, Sasaki N, Mizukami S. A Cell-Surface-Targeted Fluorogenic Probe for Detection of Sulfatase 2 Activity. Bioconjugate Chem 36(9):1980-1986, 2025.
DOI: https://doi.org/10.1021/acs.bioconjchem.5c00251

Research Project
1.Research on Maintaining Cardiac Tissue Function and Age-Related Changes
The heart consists of many types of cells and functions. To support these functions, it constantly receives essential nutrients and quickly excretes waste products. Cardiac function is believed to decline with age. Therefore, we first examined age-related changes in the mouse heart, focusing on the glycans that cover the cell surface. This revealed spatiotemporal molecular changes within cardiac tissue (Regen Ther, 2023). Over time (with aging), we observed a decrease in sialic acid, which is located at the end of glycans that modify proteins, near the outer (left ventricular wall) and inner (papillary muscle: muscle tissue supporting the valve) regions of the mouse heart (Figure 1: Staining image of MAL-I, a lectin that recognizes terminal sialic acid). Similar results were seen in aging cultured cells derived from human cardiac tissue (Biogerontology, 2021).


Another aspect that caught our attention during this analysis was the significant quantitative change observed in the lectin GSL-IB4, which is recognized as a vascular marker (Regen Ther, 2023). The heart, where many cells work together, has a network of blood vessels throughout the tissue, and it is clear that vascular function supports cardiac function. Age-related changes in vascular function are believed to be closely linked to the roles of each cell that makes up the heart. Therefore, we are focusing our investigation on the role of blood vessels, especially capillaries, in cardiac function.
Capillaries are responsible for exchanging substances within tissues. However, the process of substance exchange in the small, thin blood vessels located deep inside tissues is not well understood. This is because they are difficult to detect even with the latest imaging technology. We conducted research to address this issue and developed a detection method for administering fluorescent molecules to mice and detecting leakage from intracardiac capillaries (Figure 2). Using this technology, we observed differences in the diffusion area of fluorescent molecules into cardiac tissue between young and old mice (Regen Ther, 2025). This suggests that nutrient diffusion into tissues decreases with age. We are currently investigating how this impacts cardiac function.


2.Research on the Mechanisms of Age-Related Disease Onset via Vascular and Vascular-Mediated Inter-Organ Interactions
Atherosclerosis is the greatest risk factor for developing cardiovascular disease in elderly people. We are investigating the process by which arteriosclerosis develops and how it leads to disease. We have first investigated the changes in molecular behavior that occur with senescence in vascular endothelial cells and vascular smooth muscle cells, the two cells that play a key role in atherosclerosis.
We have revealed that GM1, a type of glycolipid called ganglioside, increases on the surface of vascular endothelial cells due to senescence and inflammation, and is involved in the decrease of insulin signaling, which is involved in NO production (JBC, 2015; Oncotarget, 2017). Regarding vascular smooth muscle cells, we have revealed that a group of gangliosides is involved in the proliferation and migration of dedifferentiated smooth muscle cells, which are involved in the progression of atherosclerosis (Front Cell Dev Biol, 2022). It has been suggested that cell surface glycans are involved in the decline of cellular function and progression of pathologies associated with senescence. Furthermore, we focused on disease formation mediated by cell-cell interactions, and investigated changes in the expression of extracellularly secreted glycan-related factors, and discovered factors that specifically increase with senescence in each cell types. We are currently investigating one of these factors using an in vitro atherosclerosis model with co-culture systems, as well as in vivo studies using a mouse model of atherosclerosis in which the factor has been specifically knocked out in endothelial cells (Figure 3).
In the future, we hope to clarify the relationship between atherosclerosis and the factor, leading to develop prevention and treatment methods for age-related diseases accompanied by atherosclerosis.



It is known that diseases in old age develop in a complex manner. Therefore, we are exploring the relationship between aging and "organ interconnections," focusing on how organs interact through blood vessels. The connection between the heart and surrounding organs is inseparable throughout a person's life. Specifically, the effects on the lungs, which are directly linked to the heart by blood vessels, and changes in the kidneys, which release markers indicating a decline in cardiac function, are expected to be closely related to blood vessels. To better understand the relationship between aging and pathology, we aim to clarify the role of glycans not only in the "cellular society" but also in this broader "organ society."
Therefore, in addition to analyzing glycans in blood vessels, we are also examining glycan patterns in various organs, similar to the heart, to explore organ-specific changes and their links to disease. First, to understand how glycan patterns change with age in each organ, we are conducting glycan profiling on extracts from each mouse tissue. The glycan information gathered is being sequentially registered and made publicly available in the public database (LM-GlycomeAtlas ver. 2.1; https://glycosmos.org/lm_glycomeatlas/index ) (age-related changes in the heart have already been registered and published). Based on these results, we aim to identify which cells within each organ undergo age-related changes and understand their functional roles. We are especially focusing on the kidneys and lungs, which are connected to cardiac function (Figure 4).
Through these analyses, we aim to clarify the relationship between aging and cardiovascular pathology and to explain the role of glycans in the "cell society" and the "organ society."

3.Research on the Regeneration of Cardiac Tissue Function and Its Mechanisms
Research into regenerating impaired cardiac function has made significant progress recently. Treatments using artificial organs and cell transplantation therapy (called regenerative medicine) that employ stem cells with abilities to proliferate and differentiate--such as pluripotent stem cells (ES cells), iPS cells, and tissue stem cells found in various tissues like hematopoietic stem cells, mesenchymal stem cells, and neural stem cells--have already advanced from basic research to clinical stages. However, for elderly individuals who often suffer from multiple diseases, undergoing such treatments poses considerable challenges because it requires addressing multiple factors. We are conducting fundamental research to preserve and restore cardiac function without compromising the quality of life for elderly people. Additionally, we are exploring what is necessary to prevent the onset of functional decline before it begins.

References

  1. Nakamura M, Yoshida-Kikkawa Y, Sugiura K, Itakura Y, Ohse K, Sasaki N, Ito Y, Toyoda M. Assessment of permeability in deep tissue capillaries using a new method reflects the nutrient supply status in a healthy heart. Regen Ther 30:900-909, 2025.
    DOI: https://doi.org/10.1016/j.reth.2025.10.005
    Erratum: Regen Ther 30:1067-1068, 2025.
    DOI: https://doi.org/10.1016/j.reth.2025.11.001
  2. Rai D, Seko Y, Ishii T, Kaneda M, Toyoda M, Umezawa A. Linking order of RAX and OTX2 following CRX in polycistronic vectors can partially determine efficacy of direct conversion to photoreceptor-like cells in vitro. Cell Biochem Biophys in press, 2025.
    DOI: https://doi.org/10.1007/s12013-025-01921-0
  3. Ando J, Murai K, Michiyuki T, Takahashi I, Iida T, Kogo Y, Toyoda M, Saito Y, Murayama S, Kurihara M, Watanabe R. Digital SERS bioanalysis of single enzyme biomarkers. Proc Natl Acad Sci USA 122(35): e2510559122, 2025.
    DOI: https://doi.org/10.1073/pnas.2510559122
  4. Sasaki N, Kawakami K, Itakura Y, Fujita T, Miyagawa S, Ishigami T, Kubo H, Miura Y, Chiba Y. Characterization of extracellular vesicles derived from cortical bone stem cells compared with mesenchymal stem cells. Mol Cell Biochem 480(11):5861-5876, 2025.
    DOI: https://doi.org/10.1007/s11010-025-05348-2
  5. Ding Y, Kowada T, Matsui T, Sasaki N, Mizukami S. A Cell-Surface-Targeted Fluorogenic Probe for Detection of Sulfatase 2 Activity. Bioconjugate Chem 36(9):1980-1986, 2025.
    DOI: https://doi.org/10.1021/acs.bioconjchem.5c00251
  6. Umezawa A, Fukuda A, Horikawa R, Uchida H, Enosawa S, Oishi Y, Nakamura N, Sasaki K, YanagiY, Shimizu S, Nakao T, Kodama T, Sakamoto S, Hayakawa I, Akiyama S, Saku N, Miyata S, Ite K, Javaregowda PK, Toyoda M, Nonaka H, Nakamura K, Ito Y, Fukuhara Y, Miyazaki O, Nonaka S, Nakabayashi K, Haga C, Yoshioka T, Masuda A, Ohkura T, Yamazaki‑Inoue M, Machida M, Abutani‑Sakamoto R, Miyajima S, Akutsu H, Matsubara Y, Igarashi T and KasaharaM. First‑in‑human clinical study of an embryonic stem cell product for urea cycle disorders. Stem Cell Res Ther 16:120, 2025.
    DOI: https://doi.org/10.1186/s13287-025-04162-3
  7. Iida T, Ando J, Yoshimura M, Makino A, Nakano M, Kogo Y, Shinoda H, Toyoda M, Noda T, Watanabe R. Portable wide-field femtoliter-chamber imaging system for point-of-care digital bioanalysis. iScience 27(9):110868, 2024.
    DOI: https://doi.org/10.1016/j.isci.2024.110868
  8. Ito M, Katoh M, Sassa T, Ko T, Fujita K, Yamada S, Miura K, Toyoda M, Takada S, Tobita T, Katagiri M, Kubota M, Yamada T, Hatsuse S, Morita H, Ikeuchi M, Matsuura K, Umezawa A, Nomura S, Aburatani H, and Komuro I. LMNA p.Q353R mutation causes dilated cardiomyopathy through impaired vitamin D signaling. Circulation 150(12):971-974, 2024.
    DOI: https://doi.org/10.1161/CIRCULATIONAHA.124.069972
  9. Yamada S, Ko T, Ito M, Sassa T, Nomura S, Okuma H, Sato M, Imasaki T, Kikkawa S, Zhang B, Yamada T, Seki Y, Fujita K, Katoh M, Kubota M, Hatsuse S, Katagiri M, Hayashi H, Hamano M, Takeda N, Morita H, Takada S, Toyoda M, Uchiyama M, Ikeuchi M, Toyooka K, Umezawa A, Yamanishi Y, Nitta R, Aburatani H, Komuro I. TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy. Sci Adv 9(15):eade7047, 2023.
    DOI: https://doi.org/10.1126/sciadv.ade7047
  10. Itakura Y, Hasegawa Y, Kikkawa Y, Murakami Y, Sugiura K, Nagai-Okatani C, Sasaki N, Umemura M, Takahashi Y, Kimura T, Kuno A, Ishiwata T, Toyoda M. Spatiotemporal changes of tissue glycans depending on localization in cardiac aging. Regen Ther 22:68-78, 2023.
    DOI: https://doi.org/10.1016/j.reth.2022.12.009
  11. Sasaki N, Hirano K, Shichi Y, Itakura Y, Ishiwata T, Toyoda M. PRC2-dependent regulation of ganglioside expression during dedifferentiation contributes to the proliferation and migration of vascular smooth muscle cells. Front Cell Dev Biol 10:1003349, 2022.
    DOI: https://doi.org/10.3389/fcell.2022.1003349
  12. Nagai-Okatani C, Zou X, Matsuda A, Itakura Y, Toyoda M, Zhang Y, Kuno A. Tissue glycome mapping: lectin microarray-based differential glycomic analysis of formalin-fixed paraffin-embedded tissue sections. Methods Mol Biol 2460:161-180, 2022.
    DOI: https://doi.org/10.1007/978-1-0716-2148-6_10
  13. Itakura Y, Sasaki N, Toyoda M. Glycan characteristics of human heart constituent cells maintaining organ function: relatively stable glycan profiles in cellular senescence. Biogerontology 22(6):623-637, 2021.
    DOI: https://doi.org/10.1007/s10522-021-09940-z
  14. Sasaki N, Itakura Y, Mohsin S, Ishigami T, Kubo H, Chiba Y. Cell Surface and Functional Features of Cortical Bone Stem Cells. Int J Mol Sci 22:11849, 2021.
    DOI: https://doi.org/10.3390/ijms222111849
  15. Sasaki N, Toyoda M, Ishiwata T. Gangliosides as signaling regulators in cancer. Int J Mol Sci 22(10):5076, 2021. (Review)
    DOI: https://doi.org/10.3390/ijms22105076
  16. Kosugi M, Otani M, Kikkawa Y, Itakura Y, Sakai K, Ito T, Toyoda M, Sekita Y, Kimura T. Mutations of histone demethylase genes encoded by X and Y chromosomes, Kdm5c and Kdm5d, leads to noncompaction cardiomyopathy in mice. Biochem Biophys Res Commun 525(1):100-106, 2020.
    DOI: https://doi.org/10.1016/j.bbrc.2020.02.043
  17. Sasaki N, Itakura Y, Toyoda M. Rapamycin promotes endothelial-mesenchymal transition during stress-induced premature senescence through the activation of autophagy. Cell Commun Signal 18(1):43, 2020.
    DOI: https://doi.org/10.1186/s12964-020-00533-w
  18. Sasaki N, Toyoda M. Vascular diseases and gangliosides. Int J Mol Sci 20(24), E6362, 2019.　 (Review)
    DOI: https://doi.org/10.3390/ijms20246362
  19. Sasaki N, Itakura Y, Toyoda M. Gangliosides contribute to vascular insulin resistance. Int J Mol Sci 20(8):1819, 2019. (Review)
    DOI: https://doi.org/10.3390/ijms20081819
  20. Itakura Y, Sasaki N, Toyoda M. Qualitative and quantitative alterations in intracellular and membrane glycoproteins maintain the balance between cellular senescence and human aging. Aging (Albany NY), 10(8):2190-2208, 2018.
    DOI: https://doi.org/10.18632/aging.101540
  21. Miura Y, Hashii N, Ohta Y, Itakura Y, Tsumoto H, Suzuki J, Takakura D, Abe Y, Arai Y, Toyoda M, Kawasaki N, Hirose N, Endo T. Characteristic glycopeptides associated with extreme human longevity identified through plasma glycoproteomics. Biochim Biophys Acta, 1862(6):1462-1471, 2018.
    DOI: https://doi.org/10.1016/j.bbagen.2018.03.025
  22. Sasaki N, Itakura Y, Toyoda M. Ganglioside GM1 contributes to extracellular/intracellular regulation of insulin resistance, impairment of insulin signaling and down-stream eNOS activation, in human aortic endothelial cells after short- or long-term exposure to TNFα. Oncotarget, 9(5):5562-5577, 2018.
    DOI: https://doi.org/10.18632/oncotarget.23726
  23. Sasaki N, Itakura Y, Toyoda M. Sialylation regulates myofibroblast differentiation of human skin fibroblasts. Stem Cell Res Ther, 8(1):81, 2017.
    DOI: https://doi.org/10.1186/s13287-017-0534-1
  24. Zou X, Yoshida M, Nagai-Okatani C, Iwaki J, Matsuda A, Tan B, Hagiwara K, Sato T, Itakura Y, Noro E, Kaji H, Toyoda M, Zhang Y, Narimatsu H, Kuno A. A standardized method for lectin microarray-based tissue glycome mapping. Sci Rep, 7:43560, 2017.
    DOI: https://doi.org/10.1038/srep43560
  25. Itakura Y, Sasaki N, Kami D, Gojo S, Umezawa A, Toyoda M. N- and O-glycan cell surface protein modifications associated with cellular senescence and human aging. Cell Biosci, 6:14, 2016.
    DOI: https://doi.org/10.1186/s13578-016-0079-5
  26. Sasaki N, Itakura Y, Toyoda M. Ganglioside GM1 contributes to the state of insulin resistance in senescent human arterial endothelial cells. J Biol Chem, 290:25475-25486, 2015.
    DOI: https://doi.org/10.1074/jbc.M115.684274