Urolithin A Promotes Angiogenesis and Tissue Regeneration in a Full-Thickness Cutaneous Wound Model

The treatment of chronic wound is an important topic of current clinical issue. Neovascularization plays a crucial role in skin wound healing by delivering fresh nutrients and oxygen to the wound area. The aim of this study was to investigate the mechanisms of urolithin A (UA) in angiogenesis during wound healing. The results of in vitro experiments showed that treatment with UA (5–20 μM) promoted the proliferation, migration, and angiogenic capacity of HUVECs. Furthermore, we investigated the effect of UA in vivo using a full-thickness skin wound model. Subsequently, we found that UA promoted the regeneration of new blood vessels, which is consistent with the results of accelerated angiogenesis in vitro experiments. After UA treatment, the blood vessels in the wound are rapidly formed, and the deposition and remodeling process of the collagen matrix is also accelerated, which ultimately promotes the effective wound healing. Mechanistic studies have shown that UA promotes angiogenesis by inhibiting the PI3K/AKT pathway. Our study provides evidence that UA can promote angiogenesis and skin regeneration in chronic wounds, especially ischemic wounds.

[1]  Chen Wang,et al.  Hsp90 up-regulates PD-L1 to promote HPV-positive cervical cancer via HER2/PI3K/AKT pathway , 2021, Molecular Medicine.

[2]  Yan Zhang,et al.  Urolithin A suppresses glucolipotoxicity-induced ER stress and TXNIP/NLRP3/IL-1β inflammation signal in pancreatic β cells by regulating AMPK and autophagy. , 2021, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[3]  Huijun Wei,et al.  Urolithin A Inhibits Epithelial–Mesenchymal Transition in Lung Cancer Cells via P53-Mdm2-Snail Pathway , 2021, OncoTargets and therapy.

[4]  R. Ahmad,et al.  Urolithin A induces cell cycle arrest and apoptosis by inhibiting Bcl-2, increasing p53-p21 proteins and reactive oxygen species production in colorectal cancer cells , 2021, Cell Stress and Chaperones.

[5]  S. Gnyawali,et al.  Urolithin A augments angiogenic pathways in skeletal muscle by bolstering NAD+ and SIRT1 , 2020, Scientific Reports.

[6]  M. Sun,et al.  33-kDa ANXA3 isoform contributes to hepatocarcinogenesis via modulating ERK, PI3K/Akt-HIF and intrinsic apoptosis pathways , 2020, Journal of advanced research.

[7]  Jingping Liu,et al.  Extracellular Vesicle-Based Therapeutics for the Regeneration of Chronic Wounds: Current Knowledge and Future Perspectives , 2020, Acta biomaterialia.

[8]  K. Kamalasanan,et al.  Drug delivery to optimize angiogenesis imbalance in keloid: A review. , 2020, Journal of controlled release : official journal of the Controlled Release Society.

[9]  M. Khorram,et al.  Vascularization strategies for skin tissue engineering. , 2020, Biomaterials science.

[10]  L. Cai,et al.  Paeoniflorin promotes angiogenesis and tissue regeneration in a full‐thickness cutaneous wound model through the PI3K/AKT pathway , 2020, Journal of cellular physiology.

[11]  Zhenzhong Zhu,et al.  A free-standing multilayer film as a novel delivery carrier of platelet lysates for potential wound-dressing applications. , 2020, Biomaterials.

[12]  Zengjie Zhang,et al.  Urolithin A-induced mitophagy suppresses apoptosis and attenuates intervertebral disc degeneration via the AMPK signaling pathway. , 2020, Free radical biology & medicine.

[13]  Min Zhang,et al.  Triclosan stimulates human vascular endothelial cell injury via repression of the PI3K/Akt/mTOR axis. , 2020, Chemosphere.

[14]  Ke-He Yu,et al.  Urolithin A targets the PI3K/Akt/NF-κB pathways and prevents IL-1β-induced inflammatory response in human osteoarthritis: in vitro and in vivo studies. , 2019, Food & function.

[15]  Sujit Maiti,et al.  Mir526b and Mir655 Promote Tumour Associated Angiogenesis and Lymphangiogenesis in Breast Cancer , 2019, Cancers.

[16]  G. Hu,et al.  RXRα provokes tumor suppression through p53/p21/p16 and PI3K-AKT signaling pathways during stem cell differentiation and in cancer cells , 2018, Cell Death & Disease.

[17]  Huazi Xu,et al.  Upregulating mTOR/ERK signaling with leonurine for promoting angiogenesis and tissue regeneration in a full-thickness cutaneous wound model. , 2018, Food & function.

[18]  Lianfeng Zhang,et al.  Dhcr24 activates the PI3K/Akt/HKII pathway and protects against dilated cardiomyopathy in mice , 2018, Animal models and experimental medicine.

[19]  Huazi Xu,et al.  Monotropein promotes angiogenesis and inhibits oxidative stress‐induced autophagy in endothelial progenitor cells to accelerate wound healing , 2017, Journal of cellular and molecular medicine.

[20]  Pascal Furet,et al.  Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors. , 2016, ACS medicinal chemistry letters.

[21]  Xiaobing Fu,et al.  Impaired wound healing results from the dysfunction of the Akt/mTOR pathway in diabetic rats. , 2015, Journal of dermatological science.

[22]  T. Giordano,et al.  Nitrite Anion Therapy Protects Against Chronic Ischemic Tissue Injury in db/db Diabetic Mice in a NO/VEGF-Dependent Manner , 2013, Diabetes.

[23]  J. Gutkind,et al.  Exploiting PI3K/mTOR signaling to accelerate epithelial wound healing. , 2013, Oral diseases.

[24]  Tyler T. Risom,et al.  Discovery and SAR of spirochromane Akt inhibitors. , 2011, Bioorganic & medicinal chemistry letters.

[25]  O. Stojadinović,et al.  Mechanism of sustained release of vascular endothelial growth factor in accelerating experimental diabetic healing. , 2009, Journal of Investigative Dermatology.

[26]  Sabine Werner,et al.  Keratinocyte-fibroblast interactions in wound healing. , 2007, The Journal of investigative dermatology.

[27]  J. Huot,et al.  Endothelial cell migration during angiogenesis. , 2007, Circulation research.

[28]  M. V. Dinther,et al.  BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis , 2007, Journal of Cell Science.

[29]  S. Leivonen,et al.  Smad3 and extracellular signal-regulated kinase 1/2 coordinately mediate transforming growth factor-beta-induced expression of connective tissue growth factor in human fibroblasts. , 2005, The Journal of investigative dermatology.

[30]  A. Schor,et al.  Growth factors in the treatment of diabetic foot ulcers , 2003, The British journal of surgery.

[31]  C. Bachert,et al.  Wound Healing of the Nasal and Paranasal Mucosa: A Review , 2002, American journal of rhinology.

[32]  R. Kirsner,et al.  Chronic venous insufficiency and venous leg ulceration. , 2001, Journal of the American Academy of Dermatology.

[33]  Paul Martin,et al.  Wound Healing--Aiming for Perfect Skin Regeneration , 1997, Science.

[34]  S. Werner,et al.  Wound repair and regeneration , 1994, Nature.

[35]  J. Raffetto,et al.  Chronic venous insufficiency. , 2014, Circulation.

[36]  J. Gutkind,et al.  Exploiting PI 3 K / mTOR signaling to accelerate epithelial wound healing , 2013 .

[37]  M. Wigand,et al.  Normal wound healing of the paranasal sinuses: Clinical and experimental investigations , 2005, European Archives of Oto-Rhino-Laryngology.

[38]  J. Folkman Angiogenesis in cancer, vascular, rheumatoid and other disease , 1995, Nature Medicine.