婴幼儿血管瘤多维代谢演进及调控机制研究进展

doi:10.19438/j.cjoms.2026.05.012

摘要/Abstract

摘要： 婴幼儿血管瘤（infantile hemangioma, IH）的演进由复杂的代谢重编程网络驱动。在机制层面,血管瘤内皮细胞（hemangioma endothelial cells, HemECs）通过6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶3（6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, PFKFB3）介导的糖酵解极化、谷氨酰胺回补及SRY-box转录因子18（SRY-box transcription factor 18, SOX18）-甲羟戊酸轴的异常激活,构建其增殖的生化动力。在调控层面,缺氧诱导因子1α（hypoxia-inducible factor-1α, HIF-1α）与哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）轴介导的转录重组是代谢转化的核心,而由干细胞、周细胞及免疫细胞构成的微环境则通过外泌体与底物穿梭实现能量共享。解析这一多组分细胞交织的动态代谢网络,不仅有助于阐明IH自发消退的生化本质,更为靶向代谢脆弱点的精准干预提供了新的思路。

关键词: 婴幼儿血管瘤, 代谢重编程, 内皮细胞, 微环境

Abstract: Infantile hemangioma (IH) evolution is fundamentally driven by integrated metabolic reprogramming. Hemangioma endothelial cells (HemECs) sustain rapid proliferation via 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) dependent glycolysis, glutamine metabolism, and the SRY-box transcription factor 18 (SOX18)-mevalonate pathway. This metabolic shift is transcriptionally regulated by the hypoxia-inducible factor-1α (HIF-1α)/ mammalian target of rapamycin (mTOR) axis and supported by a complex microenvironment where stem cells and pericytes enable energy sharing through exosomal and substrate shuttling. Decoding this multicellular metabolic network is crucial for understanding the biochemical mechanisms of IH involution and establishing new therapeutic strategies centered on metabolic vulnerability.

Key words: Infantile hemangioma, Metabolic reprogramming, Endothelial cells, Microenvironment

中图分类号:

金颂, 吴海威, 张东升. 婴幼儿血管瘤多维代谢演进及调控机制研究进展[J]. 中国口腔颌面外科杂志, 2026, 24(5): 517-526.

Jin Song, Wu Haiwei, Zhang Dongsheng. Advances in multidimensional metabolic evolution and regulatory mechanisms of infantile hemangioma[J]. China J Oral Maxillofac Surg, 2026, 24(5): 517-526.

参考文献

[1] Li W, Kang J, Bai S, et al.Skin sequelae in patients with infantile hemangioma: a systematic review[J]. Eur J Pediatr, 2023, 182(2):479-488.
[2] Rešic A, Barcot Z, Habek D, et al.The evaluation, diagnosis, and management of infantile hemangiomas-a comprehensive review[J]. J Clin Med, 2025, 14(2):425.
[3] Anderson KR, Schoch JJ, Lohse CM, et al.Increasing incidence of infantile hemangiomas (IH) over the past 35 years: correlation with decreasing gestational age at birth and birth weight[J]. J Am Acad Dermatol, 2016, 74(1):120-126.
[4] Sun Y, Zhao J, Meng Y, et al.The prevalence, complications, and risk factors for infantile hemangioma: a systematic review and meta-analysis[J]. Int J Dermatol, 2024, 63(6): 737-746.
[5] De Jong S, Itinteang T, Withers AH, et al.Does hypoxia play a role in infantile hemangioma?[J]. Arch Dermatol Res, 2016, 308(4): 219-227.
[6] Sun Y, Qiu F, Hu C, et al.Hemangioma endothelial cells and hemangioma stem cells in infantile hemangioma[J]. Ann Plast Surg, 2022, 88(2): 244-249.
[7] Maimaiti A, Aierken Y, Zhou L, et al.Inhibiting interleukin-6/signal transducers and activators of transduction-3/hypoxia-inducible factor-1α signaling pathway suppressed the growth of infantile hemangioma[J]. Eur J Pediatr Surg, 2023, 33(2): 158-166.
[8] Wang W, Chen S, Wang Y, et al.Effects of Notch signaling on proliferation, angiogenesis, and adipogenesis of hemangioma-derived stem cells[J]. Eur J Histochem, 2025, 69(3):4241.
[9] Heredea RE, Melnic E, Cirligeriu LE, et al.VEGF pathway gene expression profile of proliferating versus involuting infantile hemangiomas: preliminary evidence and review of the literature[J]. Children, 2022, 9(6):908.
[10] Makkeyah SM, Elseedawy ME, Abdel-Kader HM, et al.Vascular endothelial growth factor response with propranolol therapy in patients with infantile hemangioma[J]. Pediatr Hematol Oncol, 2022, 39(3):215-224.
[11] Xiang S, Gong X, Qiu T, et al.Insights into the mechanisms of angiogenesis in infantile hemangioma[J]. Biomed Pharmacother, 2024, 178:117181.
[12] Liu L, Yu J, Liu Y, et al.Hypoxia-driven angiogenesis and metabolic reprogramming in vascular tumors[J]. Front Cell Dev Biol, 2025, 13: 1572909.
[13] Liu Y, Wu Z, Li Y, et al.Metabolic reprogramming and interventions in angiogenesis[J]. J Adv Res, 2025, 70:323-338.
[14] Peng H, Wang X, Du J, et al.Metabolic reprogramming of vascular endothelial cells: basic research and clinical applications[J]. Front Cell Dev Biol, 2021, 9:626047.
[15] Citrin KM, Chaube B, Fernández-Hernando C, et al.Intracellular endothelial cell metabolism in vascular function and dysfunction[J]. Trends Endocrinol Metab, 2025, 36(8): 744-755.
[16] Yang K, Qiu T, Gong X, et al.Integrated nontargeted and targeted metabolomics analyses amino acids metabolism in infantile hemangioma[J]. Front Oncol, 2023, 13:1132344.
[17] Chen J, Wu D, Dong Z, et al.The expression and role of glycolysis-associated molecules in infantile hemangioma[J]. Life Sci, 2020, 259:118215.
[18] 杨开颖. 糖酵解关键酶在婴幼儿血管瘤中的表达及作用机制研究[D]. 成都:四川大学,2022.
Yang KY.Study on the expression and mechanism of key enzymes of glycolysis in infantile hemangioma[D]. Chengdu: Sichuan University, 2022.
[19] Yang K, Qiu T, Zhou J, et al.Blockage of glycolysis by targeting PFKFB3 suppresses the development of infantile hemangioma[J]. J Transl Med, 2023, 21: 85.
[20] 向姗姗, 龚雪, 周江元, 等. 靶向抑制PFKFB3 对婴幼儿血管瘤内皮细胞糖代谢的影响研究[J]. 临床小儿外科杂志,2025, 24(10): 981-987.
Xiang SS, Gong X, Zhou JY, et al.Effects of glucose metabolism through a targeted inhibition of PFKFB3 on hemangioma-derived endothelial cell[J]. Journal of Clinical Pediatric Surgery, 2025, 24(10): 981-987.
[21] Yang K, Zhang X, Chen L, et al.Microarray expression profile of mRNAs and long noncoding RNAs and the potential role of PFK-1 in infantile hemangioma[J]. Cell Div, 2021, 16: 1.
[22] Eniafe J, Jiang S.The functional roles of TCA cycle metabolites in cancer[J]. Oncogene, 2021, 40(19):3351-3363.
[23] Meng Q, Zhang Y, Hao S, et al.Recent findings in the regulation of G6PD and its role in diseases[J]. Front Pharmacol, 2022, 13:932154.
[24] Holm A, Graus MS, Wylie-Sears J, et al.An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma[J]. J Clin Invest, 2025, 135(7): e179782.
[25] Iruela-Arispe ML.Unveiling the cholesterol-hemangioma axis: a path to new treatments[J]. J Clin Invest, 2025, 135(7):e193039.
[26] Tan JWH, Wylie-Sears J, Seebauer CT, et al.R(+) propranolol decreases lipid accumulation in hemangioma-derived stem cells[J]. Br J Dermatol, 2025, 192(4): 757-759.
[27] Chen S, Wang R, Guo Y, et al.R-propranolol promotes the adipogenesis and subsequent apoptosis of hemangioma stem cells through the protein kinase RNA-like endoplasmic reticulum kinase signaling pathway[J]. Am J Pathol, 2026, 196(6):1389-1401.
[28] Wang F, Li H, Lou Y, et al.Insulin-like growth factor I promotes adipogenesis in hemangioma stem cells from infantile hemangiomas[J]. Mol Med Rep, 2019, 19(4):2825-2830.
[29] Clémot M, Sênos Demarco R, Jones DL.Lipid mediated regulation of adult stem cell behavior[J]. Front Cell Dev Biol, 2020, 8:115.
[30] Giger S, Kovtonyuk LV, Utz SG, et al.A single metabolite which modulates lipid metabolism alters hematopoietic stem/progenitor cell behavior and promotes lymphoid reconstitution[J]. Stem Cell Rep, 2020, 15(3):566-576.
[31] Lai Y, Tian Y, You X, et al.Effects of sphingolipid metabolism disorders on endothelial cells[J]. Lipids Health Dis, 2022, 21: 101.
[32] Sasset L, Di Lorenzo A.Sphingolipid metabolism and signaling in endothelial cell functions[J]. Adv Exp Med Biol, 2022, 1372:87-117.
[33] Durante W.The emerging role of l-Glutamine in cardiovascular health and disease[J]. Nutrients, 2019, 11(9): 2092.
[34] Jin J, Byun JK, Choi YK, et al.Targeting glutamine metabolism as a therapeutic strategy for cancer[J]. Exp Mol Med, 2023, 55(4):706-715.
[35] Song J, Kang SM, Lee WT, et al.Glutathione protects brain endothelial cells from hydrogen peroxide-induced oxidative stress by increasing Nrf2 expression[J]. Exp Neurobiol, 2014, 23(1):93-103.
[36] Wang J, Da X, Chen Y, et al.Glutamine protects against mouse abdominal aortic aneurysm through modulating VSMC apoptosis and M1 macrophage activation[J]. Int J Med Sci, 2024, 21(8): 1414-1427.
[37] Kim B, Li J, Jang C, et al.Glutamine fuels proliferation but not migration of endothelial cells[J]. EMBO J, 2017, 36(16): 2321-2333.
[38] Zuccolo E, Bottino C, Diofano F, et al.Constitutive store-operated Ca²+ entry leads to enhanced nitric oxide production and proliferation in infantile hemangioma-derived endothelial colony-forming cells[J]. Stem Cells Dev, 2016, 25(4):301-319.
[39] Rohlenova K, Veys K, Miranda-Santos I, et al.Endothelial cell metabolism in health and disease[J]. Trends Cell Biol, 2018, 28(3): 224-236.
[40] Xu K, Shah P, Makhanasa D, et al.Unveiling the maze: branched-chain amino acids fueling the dynamics of cancer metabolism and progression[J]. Cancers, 2025, 17(11): 1751.
[41] Mirando AC, Fang P, Williams TF, et al.Aminoacyl-tRNA synthetase dependent angiogenesis revealed by a bioengineered macrolide inhibitor[J]. Sci Rep, 2015, 5: 13160.
[42] Pan X, Hui H, Teng X, et al.Overexpression of Annexin A1 is associated with the formation of capillaries in infantile hemangioma[J]. Mol Clin Oncol, 2022, 17(3): 133.
[43] Zhang W, Sun L, Gao H, et al.Mechanism of the HIF-1α/VEGF/VEGFR-2 pathway in the proliferation and apoptosis of human haemangioma endothelial cells[J]. Int J Exp Pathol, 2023, 104(5): 258-268.
[44] Basheeruddin M, Qausain S.Hypoxia-inducible factor 1-alpha (HIF-1α): an essential regulator in cellular metabolic control[J]. Cureus, 2024, 16(7): e63852.
[45] Sato T, Takeda N.The roles of HIF-1α signaling in cardiovascular diseases[J]. J Cardiol, 2023, 81(2): 202-208.
[46] Song S, Zhang G, Chen X, et al.HIF-1α increases the osteogenic capacity of ADSCs by coupling angiogenesis and osteogenesis via the HIF-1α/VEGF/AKT/mTOR signaling pathway[J]. J Nanobiotechnol, 2023, 21(1): 257.
[47] Chen G, Zhang W, Li YP, et al.Hypoxia-induced autophagy in endothelial cells: a double-edged sword in the progression of infantile haemangioma?[J]. Cardiovasc Res, 2013, 98(3): 437-448.
[48] Kleinman EP, Blei F, Adams D, et al.Sirolimus for diffuse intestinal infantile hemangioma with PHACE features: systematic review[J]. Pediatr Res, 2023, 93(6): 1470-1479.
[49] Holm A, Mulliken JB, Bischoff J.Infantile hemangioma: the common and enigmatic vascular tumor[J]. J Clin Invest, 2024, 134(8): e172836.
[50] Boscolo E, Mulliken JB, Bischoff J.Pericytes from infantile hemangioma display proangiogenic properties and dysregulated angiopoietin-1[J]. Arterioscler Thromb Vasc Biol, 2013, 33(3): 501-509.
[51] Xia M, Liu W, Hou F.Mast cell in infantile hemangioma[J]. Front Oncol, 2024, 14: 1304478.
[52] Ye Y, Zhong H, Dou L, et al.Propranolol inhibits the angiogenic capacity of hemangioma endothelia via blocking β-adrenoceptor in mast cell[J]. Pediatr Res, 2022, 92(2): 424-429.
[53] Boutilier AJ, Elsawa SF.Macrophage polarization states in the tumor microenvironment[J]. Int J Mol Sci, 2021, 22(13): 6995.
[54] Dodson M, Castro-Portuguez R, Zhang DD.NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis[J]. Redox Biol, 2019, 23: 101107.
[55] Yuan SM, Guo Y, Xu Y, et al.The adipogenesis in infantile hemangioma and the expression of adipogenic-related genes[J]. Int J Clin Exp Pathol, 2017, 10(12): 11596-11602.
[56] Mitra R, Fitzsimons HL, Hale T, et al.Recent advances in understanding the molecular basis of infantile haemangioma development[J]. Br J Dermatol, 2024, 191(5): 661-669.
[57] Liang T, Liu X, Tong Y, et al.Recent advances in targeted therapies for infantile hemangiomas[J]. Int J Nanomed, 2024, 19: 6127-6143.
[58] Tan S, Yang Y, Yang W, et al.Exosomal cargos-mediated metabolic reprogramming in tumor microenvironment[J]. J Exp Clin Cancer Res, 2023, 42(1): 59.
[59] Yang K, Li X, Qiu T, et al.Effects of propranolol on glucose metabolism in hemangioma-derived endothelial cells[J]. Biochem Pharmacol, 2023, 218: 115922.
[60] Harasim G, Frańczak MA, Minutolo F, et al.Effects of lactate dehydrogenase A and GLUT1 inhibition on human endothelial cell migration in relation to their intracellular nucleotide pool[J]. Nucleosides Nucleotides Nucleic Acids, 2024, 43(8): 761-769.
[61] Peng K, Xia R, Zhao F, et al.HECW2 knockdown suppresses the development of infantile hemangioma by inhibiting ALKBH5/LDHA axis-mediated glycolysis[J]. Am J Cancer Res, 2025, 15(5): 2041-2055.
[62] Ngwa VM, Edwards DN, Hwang Y, et al.Loss of vascular endothelial glutaminase inhibits tumor growth and metastasis, and increases sensitivity to chemotherapy[J]. Cancer Res Commun, 2022, 2(7): 694-705.
[63] Morozumi K, Kawasaki Y, Sakamoto I, et al.Glutaminase inhibition confers antitumor effects in vitro and in vivo on tyrosine kinase inhibitors-resistant renal cell carcinoma cells by affecting vascular endothelial growth factor signaling[J]. Biomed Pharmacother, 2025, 191: 118492.
[64] Overman J, Fontaine F, Wylie-Sears J, et al.R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma[J]. eLife, 2019, 8: e43026.
[65] Mabray MC, Caprihan A, Nelson J, et al.Effect of simvastatin on permeability in cerebral cavernous malformation type 1 patients: results from a pilot small randomized controlled clinical trial[J]. Transl Stroke Res, 2020, 11(3): 319-321.
[66] Abtahi-Naeini B, Ahmadinia F, Ghorbali F, et al.A Systematic review of the efficacy and safety of sirolimus (rapamycin) in the management of infantile hemangioma[J]. J Res Pharm Pract, 2025, 14(4): 127-133.
[67] Lopes F, Levy ML, Ruth JS, et al.Sirolimus in the management of complex infantile hemangiomas: a state-of-the-art review[J]. Pediatr Dermatol, 2025, 42(6): 1126-1132.
[68] Greenberger S, Yuan S, Walsh LA, et al.Rapamycin suppresses self-renewal and vasculogenic potential of stem cells isolated from infantile hemangioma[J]. J Invest Dermatol, 2011, 131(12): 2467-2476.
[69] Le Sage S, David M, Dubois J, et al.Efficacy and absorption of topical sirolimus for the treatment of vascular anomalies in children: a case series[J]. Pediatr Dermatol, 2018, 35(4): 472-477.
[70] Dávila-Osorio VL, Iznardo H, Roé E, et al.Propranolol-resistant infantile hemangioma successfully treated with sirolimus[J]. Pediatr Dermatol, 2020, 37(4): 684-686.
[71] Cho YJ, Kwon H, Kwon YJ, et al.Effects of sirolimus in the treatment of unresectable infantile hemangioma and vascular malformations in children: a single-center experience[J]. J Vasc Surg Venous Lymphat Disord, 2021, 9(6): 1488-1494.
[72] Jiang CH, Lin PF, Chen FC, et al.Metabolic profiling revealed prediction biomarkers for infantile hemangioma in umbilical cord blood sera: a prospective study[J]. J Proteome Res, 2022, 21(3): 822-832.
[73] Wang Y, Liu W, Wang J, et al.TMT-based serum proteomics analysis of infantile hemangioma patients[J]. Minerva Pediatr, 2024, 76(4): 566-568.
[74] Cakmak HM, Kiliccioglu I, Dulger G.Dynamic serum biomarkers in infantile hemangioma: the role of VEGF-B, AKT, and eNOS in lesion regression[J]. Eur J Pediatr, 2025, 184: 476.
[75] 袁尉力, 王绪凯. 口服普萘洛尔对增殖期血管瘤患儿尿液bFGF、MMP-2和MMP-9表达水平的影响[J]. 上海口腔医学, 2022, 31(4): 400-405.
Yuan WL, Wang XK.Effects of oral propranolol on urine bFGF, MMP-2, MMP-9 expression in children with proliferative infantile hemangioma[J]. Shanghai Kou Qiang Yi Xue, 2022, 31(4):400-405.
[76] Xu G, Sun J, Wei L, et al.HOXD9 enhances the release of HMGB1 and boosts glycolysis in glioblastoma under hypoxic conditions, leading to tumor growth by activating the transcription of PFKFB3[J]. Front Biosci(Landmark Ed), 2024, 29(10): 341.
[77] Fu Y, Wang D, Wang H, et al.TSPO deficiency induces mitochondrial dysfunction, leading to hypoxia, angiogenesis, and a growth-promoting metabolic shift toward glycolysis in glioblastoma[J]. Neuro Oncol, 2020, 22(2): 240-252.
[78] Mazumder S, Higgins PJ, Samarakoon R.Downstream targets of VHL/HIF-α signaling in renal clear cell carcinoma progression: mechanisms and therapeutic relevance[J]. Cancers, 2023, 15(4): 1316.
[79] Wang T, Rao D, Yu C, et al.RHO GTPase family in hepatocellular carcinoma[J]. Exp Hematol Oncol, 2022, 11: 91.