Poly-D,L-Lactic Acid Stimulates Angiogenesis and Collagen Synthesis in Aged Animal Skin

• Published in: International journal of molecular sciences Vol. 24; no. 9; p. 7986
• Main Authors: Oh, Seyeon, Seo, Suk Bae, Kim, Gunpoong, Batsukh, Sosorburam, Son, Kuk Hui, Byun, Kyunghee
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.04.2023; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; Acids; aged skin; Aging; AKT protein; Analysis; Angiogenesis; Animal skins; Animals; Care and treatment; Cell proliferation; Collagen; Cytokines; Dermal fillers; Endothelial cells; Endothelial Cells - metabolism; Endothelium; Extracellular signal-regulated kinase; Fibroblasts; Growth factors; heat shock protein 90; Heat shock proteins; Hsp90 protein; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Hydroxyapatite; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Kinases; Lactic acid; Macrophages; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic - metabolism; Oxidative stress; Phosphatidylinositol 3-Kinase - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Poly-D,L-Lactic acid filler; Polylactic acid; Proto-Oncogene Proteins c-akt - metabolism; Scientific equipment and supplies industry; Skin; Skin Aging; skin rejuvenation; Transforming growth factors; Tumor necrosis factor-TNF; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; South Korea; United States; Japan; China; Missouri; Maryland; Germany; collagen; aged skin; skin rejuvenation; angiogenesis; heat shock protein 90; Poly-D,L-Lactic acid filler
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24097986

Angiogenesis promotes rejuvenation in multiple organs, including the skin. Heat shock protein 90 (HSP90), hypoxia-inducible factor-1 alpha (HIF-1α), and vascular endothelial growth factor (VEGF) are proangiogenic factors that stimulate the activities of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and extracellular signal-regulated kinase 1/2 (ERK1/2). Poly-D,L-lactic acid (PDLLA), polynucleotide (PN), and calcium hydroxyapatite (CaHA) are dermal fillers that stimulate the synthesis of dermal collagen. However, it is not yet known whether these compounds promote angiogenesis, which leads to skin rejuvenation. Here, we evaluated whether PDLLA, PN, and CaHA stimulate angiogenesis and skin rejuvenation using H O -treated senescent macrophages and endothelial cells as an in vitro model for skin aging, and we used young and aged C57BL/6 mice as an in vivo model. Angiogenesis was evaluated via endothelial cell migration length, proliferation, and tube formation after conditioned media (CM) from senescent macrophages was treated with PDLLA, PN, or CaHA. Western blot showed decreased expression levels of HSP90, HIF-1α, and VEGF in senescent macrophages, but higher expression levels of these factors were found after treatment with PDLLA, PN, or CaHA. In addition, after exposure to CM from senescent macrophages treated with PDLLA, PN, or CaHA, senescent endothelial cells expressed higher levels of VEGF receptor 2 (VEGFR2), PI3K, phosphorylated AKT (pAKT), and phosphorylated ERK1/2 (pERK1/2) and demonstrated greater capacities for cell migration, cell proliferation, and tube formation. Based on the levels of 4-hydroxy-2-nonenal, the oxidative stress level was lower in the skin of aged mice injected with PDLLA, PN, or CaHA, while the tumor growth factor (TGF)-β1, TGF-β2, and TGF-β3 expression levels; the density of collagen fibers; and the skin elasticity were higher in the skin of aged mice injected with PDLLA, PN, or CaHA. These effects were greater in PDLLA than in PN or CaHA. In conclusion, our results are consistent with the hypothesis that PDLLA stimulates angiogenesis, leading to the rejuvenation of aged skin. Our study is the first to show that PDLLA, PN, or CaHA can result in angiogenesis in the aged skin, possibly by increasing the levels of HSP90, HIF-1α, and VEGF and increasing collagen synthesis.