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. Author manuscript; available in PMC: 2023 Sep 1.
Published in final edited form as: Eng Regen. 2023 Mar 31;4(3):265–276. doi: 10.1016/j.engreg.2023.03.008

Table 1.

Summaries of proangiogenic metals and their signaling pathways.

Metal Mechanism of
action		 Nanomaterial
format		 Experimental
methods		 Method of
fabrication		 Nanomaterial
concentrations
tested		 References
Terbium NADPH oxidase-mediated PI3K/AKT activation, ROS accumulation Layered terbium(III) hydroxide (Tb(OH)3) nanorods, Tb(OH)3 nanospheres Sprouting and proangiogenesis fluorescence by an in vivo zebrafish embryo assay Reaction of aqueous terbium(III) nitrate hydrate and NH4OH with SINEO-MAS II, reaction of TbCl3 hydrate and NaCl/NaOH at 60°C 5–10 μg/mL [88]-[91]
Europium PI3K/AMPK/Akt activation, inhibition of TNF-α and IL-6, upregulation of CD31 Europium(III) hydroxide (Eu(OH)3) nanorods, Eu(OH)3 nanospheres Sprouting and proangiogenesis fluorescence by an in vivo zebrafish embryo assay Simple microwave heating of an aqueous solution of europium(III) nitrate and NH4H2PO4 20–50 μg/mL [92]-[96], [125]
Cerium Upregulation of HIF-1α, enhanced VEGF mRNA translation Ce3+/Ce4+ containing oxide In vitro endothelial tube formation assay, branch number measured by an in vivo CAM assay Flame spray pyrolysis of cerium-containing liquid precursor and cerium 2-ethylhexanoate in xylene 50 μg/mL [97]-[99]
Copper VEGF-A and FGF2 upregulation, enhanced expression of PCNA, MyoD1 Copper hydrocolloid nanospheres Vessel length and branch number measured by an in vivo CAM assay Copper oxide impregnation of wound dressing fibers 0.1–10 μM [101], [104], [105]
Cobalt Activation of AKT/ERK1/2, transcriptional activation of NF-κB, AP-1 and VEGF Tungsten carbide-cobalt nanoparticles VEGF secretion measured in vitro, neovascularization measured in vivo with HUVEC Sol-gel method with tetraethyl orthosilicate, triethyl phosphate, Ca(NO3)2, and CoCl2, and nitric acid 1,000–2,000 μg/mL [106]-[108]
Zinc ROS production, VEGF and FGF upregulation, ZnR/GPR39, Gq-PLC, and MAPK-Akt-eNOS activation Zinc oxide (ZnO) nanoflowers, ZnO nanorods Vessel branch number measured by an in vivo CAM assay Sol-gel method with Zn(CH3COO)2 and albumin in ultrapure water 10–50 μg/mL [102], [109]-[111]
Nickel Release of HIF-1, IL-6, c-IAP, BCL-2, ICAM-1, IL-1β, and Cox-2 Nickel titanium nanoparticles Measurement of angiogenic potential in athymic (T cell-deficient) nude mice Prepared via laser evaporation of NiTi alloy, nanoparticles heat-treated at 250°C and resuspended in LAL reagent water 0.25–0.75 mM [12], [112]
Magnesium MC3T3-E1 expression, PDGF-BB secretion Mg2+ ions Angiogenic potential measured by in vivo CAM assay, cytocompatibility measured in vitro with MC3T3-E1 Hydroxyapatite and MgO added to sodium alginate solution, and extruded to CaCl2 1–5 mM [103], [113]-[115]
Lithium Augmentation of Wnt/β-catenin in Norrin/Frizzled-4, VEGF secretion through the phosphorylation of glycogen synthase kinase-3β (GSK-3β) Li+ (in the form of LiCl) In vitro measurement of proangiogenic factors (VEGF) secretion by BMSC LiCl in serum-free medium 0.2–20 mM [116]-[119]
Cadmium Enhanced VEGF expression, activation of PKB/Akt, NF-κB, MAPK, and ERK/AKT Ultralow concentrations of elemental cadmium In vitro measurement of endothelial structure formation with HUVEC Cadmium chloride in basal media 1–10 μM [120]-[122]
Chromium Enhance promoters for proangiogenic transcription factors such as NF-κB, p53, and c-Fos Hexavalent chromium (Cr(VI)) compounds In vitro measurement of proangiogenic miR-143 and miR-145 in Cr(VI)-transformed cells Chromium nanomaterial in the form of Cr(VI) oxidation state 1–10 μM [123]