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基于Tie2/Ang/VE-cadherin信号轴研究阿胶改善D-半乳糖诱导的皮肤衰老和微血管稳态的作用机制

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赵钰佳 ¹,,² , 孙娅楠 ¹, , 高欣雨 ¹,,² , 刘海滨 ³ , 王毅 ¹,

中草药 | 药理与临床 2026,57(16): 6371-6384

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中草药 |药理与临床 2026 , 57 (16) : 6371 -6384

基于Tie2/Ang/VE-cadherin信号轴研究阿胶改善D-半乳糖诱导的皮肤衰老和微血管稳态的作用机制

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赵钰佳¹,,², 孙娅楠¹,, 高欣雨¹,,², 刘海滨³, 王毅¹,

作者信息

^1.中国中医科学院医学实验中心, 北京 100700

^2.沈阳药科大学中药学院, 辽宁沈阳 110016

^3.东阿阿胶股份有限公司国家胶类中药工程技术研究中心, 山东聊城 252200

^4.中国中医科学院医学实验中心, 北京 100700

通讯作者:

刘海滨

作者简介:

赵钰佳: 赵钰佳,硕士研究生,研究方向为中药新疗效的开发。E-mail:rangers1120@163.com

Mechanism of Colla Corii Asini on improving D-galactose-induced skin aging and microvascular homeostasis based on Tie2/Ang/VE-cadherin signal axis

Affiliations

出版时间: 2026-08-28 doi: 10.7501/j.issn.0253-2670.2026.16.013

文章导航

摘要

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目的探讨阿胶在延缓D-半乳糖诱导的皮肤衰老及维持微血管稳态方面的药效作用，并阐明其通过酪氨酸激酶受体2（tyrosine kinase with immunoglobulin-like and EGF-like domains 2，Tie2）/血管生成素（angiopoietin，Ang）/血管内皮钙黏蛋白（vascular endothelial cadherin，VE-cadherin）信号轴调控血管成熟度的分子机制。方法采用sc D-半乳糖构建小鼠早衰模型，连续8周ig给予阿胶（270.3 mg/kg）干预，通过激光散斑血流成像（laser speckle contrast imaging，LSCI）监测背部血流，光相干断层扫描血管造影（optical coherence tomography angiography，OCTA）观察微血管密度，苏木素-伊红（hematoxylin-eosin staining，HE）及Masson染色评估皮肤组织形态及胶原含量，免疫荧光及免疫组化检测皮肤组织血管内皮标志物CD31和周细胞标志物血小板源生长因受体β（platelet-derived growth factor receptor β，PDGFRβ）的表达，采用ELISA检测血清Ang1/Ang2的值，采用qRT-PCR检测皮肤组织白细胞介素-1β（interleukin-1β，IL-1β）、趋化因子配体1（C-X-C motif chemokine ligand 1，CXCL1）和肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）mRNA表达。采用过氧化氢（hydrogen peroxide，H₂O₂）诱导人脐静脉内皮细胞（human umbilical vein endothelial cells，HUVEC）构建应激性早衰模型，给予62.5～250.0 μg/mL阿胶预处理24 h，通过CCK-8检测细胞活力，通过衰老相关β-半乳糖苷酶（senescence-associated β-galactosidase，SA-β-gal）染色及活性氧（reactive oxygen species，ROS）水平评估衰老程度，qRT-PCR检测衰老相关分泌表型（senescence-associated secretory phenotype，SASP）及炎症相关基因表达，Western blotting检测肿瘤蛋白p53（tumor protein p53，p53）、周期蛋白依赖性激酶抑制剂1A（cyclin dependent kinase inhibitor 1A，p21）、p-Tie2、Tie2、VE-cadherin、血管内皮生长因子A（vascular endothelial growth factor A，VEGFA）蛋白表达，ELISA检测Ang1/Ang2的值，通过周细胞招募及内皮渗透实验评价血管稳定性。结果动物实验中，阿胶显著改善衰老小鼠皮肤褶皱，增加表皮及真皮厚度和胶原容积分数（P＜0.01、0.001），恢复皮肤血流灌注并减少杂乱的无序血管生成，提高皮肤组织PDGFRβ的表达及血清Ang1/Ang2的值（P＜0.001），下调炎症因子表达（P＜0.001），增强血管成熟度。细胞实验中，阿胶显著降低HUVEC中SA-β-gal阳性率及ROS水平（P＜0.001），下调SASP及炎症相关基因表达（P＜0.01、0.001），上调p-Tie2和VE-cadherin的蛋白表达（P＜0.001），下调p53、p21、Tie2和VEGFA的蛋白表达（P＜0.05、0.001），并提高Ang1/Ang2的值（P＜0.05、0.01），显著增强内皮细胞对周细胞的招募能力及血管内皮屏障的完整性。结论阿胶可改善D-半乳糖诱导的衰老皮肤模型的衰老表型，提高微血管成熟度并维持血管稳态，其作用可能与调节Tie2/Ang/VE-cadherin信号轴有关。

关键词

阿胶 / 皮肤衰老 / 微血管稳态 / 血管成熟度 / Tie2/Ang/VE-cadherin信号轴 / 炎症反应

Abstract

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Objective To explore the pharmacological effect of Ejiao (Colla Corii Asini, CCA) on delaying D-galactose-induced skin aging and maintaining microvascular homeostasis, and to clarify the molecular mechanism of its regulation of vascular maturity through tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2)/angiopoietin (Ang)/vascular endothelial cadherin (VE-cadherin) signal axis. Methods The model of premature senility in mice was established by sc D-galactose, and CCA (270.3 mg/kg) was administered ig for eight weeks. The back blood flow was monitored by laser speckle contrast imaging (LSCI), the microvessel density was observed by optical coherence tomography angiography (OCTA), the skin tissue morphology and collagen content were evaluated by hematoxylin-eosin staining (HE) and Masson staining, the expressions of vascular endothelial marker CD31 and pericyte marker platelet-derived growth factor receptor β (PDGFRβ) were detected by immunofluorescence and immunohistochemistry, the Ang1/Ang2 value in serum was detected by ELISA, the expressions of interleukin-1β (IL-1β), C-X-C motif chemokine ligand 1 (CXCL1) and tumor necrosis factor-α (TNF-α) mRNA in skin tissue was detected by qRT-PCR. Human umbilical vein endothelial cells (HUVEC) were induced by hydrogen peroxide (H₂O₂) to construct a stress premature aging model, cells were pretreated with 62.5—250.0 μg/mL CCA for 24 h. Cell viability was detected by CCK-8. Senescence-associated β-galactosidase (SA-β-gal) staining and reactive oxygen species (ROS) level were used to assess the degree of aging. qRT-PCR was used to detect the senescence-associated secretory phenotype (SASP) and inflammation related gene expressions. Western blotting was used to detect tumor protein p53 (p53), cyclin dependent kinase inhibitor 1 A (p21), p-Tie2, Tie2, VE-cadherin and vascular endothelial growth factor A (VEGFA) protein expressions. Ang1/Ang2 value was detected by ELISA. Vascular stability was evaluated through pericyte recruitment and endothelial permeability experiments. Results In the animal experiment, CCA significantly improved the skin fold of aging mice, increased the thickness of epidermis and dermis and collagen volume fraction (P < 0.01, 0.001), restored skin blood flow perfusion and reduced disordered angiogenesis, increased the expression of PDGFRβ in skin tissue and the value of Ang1/Ang2 in serum (P < 0.001), decreased the expressions of inflammatory factors (P < 0.001), and enhanced vascular maturity. In the cell experiment, CCA significantly reduced the positive rate of SA-β-gal and ROS level in HUVEC (P < 0.001), down-regulated the expressions of SASP and inflammation related genes (P < 0.01, 0.001), up-regulated the protein expressions of p-Tie2 and VE-cadherin (P < 0.001), down-regulated the protein expressions of p53, p21, Tie2 and VEGFA (P < 0.05, 0.001), and increased the value of Ang1/Ang2 (P < 0.05, 0.01), significantly enhancing the ability of endothelial cells to recruit pericytes and the integrity of vascular endothelial barrier. Conclusion CCA can improve the aging phenotype of aging skin model induced by D-galactose, improve microvascular maturity and maintain vascular homeostasis, which may be related to the regulation of Tie2/Ang/VE-cadherin signal axis.

Key words

Colla Corii Asini / skin aging / vascular homeostasis / vascular maturation / Tie2/Ang/VE-cadherin signaling axis / inflammatory response

引用本文

赵钰佳, 孙娅楠, 高欣雨, 刘海滨, 王毅. 基于Tie2/Ang/VE-cadherin信号轴研究阿胶改善D-半乳糖诱导的皮肤衰老和微血管稳态的作用机制. 中草药, 2026 , 57 (16) : 6371 -6384 . DOI: 10.7501/j.issn.0253-2670.2026.16.013

ZHAO Yujia, SUN Yanan, GAO Xinyu, LIU Haibin, WANG Yi. Mechanism of Colla Corii Asini on improving D-galactose-induced skin aging and microvascular homeostasis based on Tie2/Ang/VE-cadherin signal axis[J]. Chinese Traditional and Herbal Drugs, 2026 , 57 (16) : 6371 -6384 . DOI: 10.7501/j.issn.0253-2670.2026.16.013

基金

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山东东阿阿胶股份有限公司研究基金资助项目
中国中医科学院科技创新工程创新能力提升专项
中央级公益性科研院所基本科研业务费专项
泰山工业专项
中央引导地方科技发展资金

参考文献

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参考文献引证文献

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Wang-Evers M, Casper M J, Glahn J, et al. Assessing the impact of aging and blood pressure on dermal microvasculature by reactive hyperemia optical coherence tomography angiography [J]. Sci Rep, 2021, 11: 13411.
Kasal D A, Sena V, Huguenin G V B, et al. Microvascular endothelial dysfunction in vascular senescence and disease [J]. Front Cardiovasc Med, 2025, 12: 1505516.
Zhang Y C, Liu J Q, Zou T, et al. DPSCs treated by TGF-β1 regulate angiogenic sprouting of three-dimensionally co-cultured HUVECs and DPSCs through VEGF-Ang-Tie2 signaling [J]. Stem Cell Res Ther, 2021, 12(1): 281.
Zhang L, Xu Z J, Jiang T, et al. Efficacy and safety of Ejiao (Asini Corii Colla) in women with blood deficient symptoms: A randomized, double-blind, and placebo-controlled clinical trial [J]. Front Pharmacol, 2021, 12: 718154.
辛睿静. 双侧颈动脉高风险斑块的MR影像特征、危险因素及其与临床症状的相关性研究[D]. 南京: 东南大学, 2021.
Gaonac’h-Lovejoy V, Boscher C, Delisle C, et al. Rap1 is involved in angiopoietin-1-induced cell-cell junction stabilization and endothelial cell sprouting [J]. Cells, 2020, 9(1): 155.
Nan W J, He Y X, Wang S R, et al. Molecular mechanism of VE-cadherin in regulating endothelial cell behaviour during angiogenesis [J]. Front Physiol, 2023, 14: 1234104.
Wakasugi R, Suzuki K, Kaneko-Kawano T. Molecular mechanisms regulating vascular endothelial permeability [J]. Int J Mol Sci, 2024, 25(12): 6415.
杨宝林. NO/NOS在侧支血管生长中对血管VE-cadherin表达及通透性的影响[D]. 长沙:中南大学, 2013.
Parikh S M. Angiopoietins and Tie2 in vascular inflammation [J]. Curr Opin Hematol, 2017, 24(5): 432-438.
Koya Y, Nara H, Yagi S, et al. An engineered tetra-valent antibody fully activates the Tie2 receptor with comparable potency to its natural ligand angiopoietin-1[J]. Sci Rep, 2021, 11: 14021.
Reglero-Real N, Rolas L, et al. Aging microvasculature:Effects on immune cell trafficking and inflammatory diseases [J]. J Exp Med, 2025, 222(7): e20242154.
Kraft M, Schoofs H, Petkova M, et al. Angiopoietin-TIE2 feedforward circuit promotes PIK3CA-driven venous malformations [J]. Nat Cardiovasc Res, 2025, 4(7): 801-820.
Liang R, Xu L, Fan C, et al. Structural characteristics and antioxidant mechanism of donkey-hide gelatin peptides by molecular dynamics simulation [J]. Molecules, 2023, 28(24): 7975.
Luo Q D, Zhang S, Sun Z, et al. Protective effects of Colla Corii Asini collagen peptides on D-galactose injection combined with UVB irradiation-induced aging in mice [J]. PLoS One, 2025, 20(2):e0317302.
Zhang J J, Lin D L, Wu Y T, et al. Blood-supplementing effect of low molecular weight peptides of E-Jiao on chemotherapy-induced myelosuppression:Evaluation of pharmacological activity and identification of bioactive peptides released in vivo [J]. Front Pharmacol, 2024, 15: 1366407.
Râpă M, Gaidau C, Stefan L M, et al. Donkey gelatin and keratin nanofibers loaded with antioxidant agents for wound healing dressings [J]. Gels, 2024, 10(6): 391.
Xu X L, Wang B, Ren C H, et al. Recent progress in vascular aging: Mechanisms and its role in age-related diseases [J]. Aging Dis, 2017, 8(4): 486.
Ma Y M, Huang J, Gong J X, et al. Colla Corii Asini regulate collagen regeneration in UV exposure-induced skin photoaging in mice [J]. Chin Med, 2025, 20(1): 146.
Gao X Y, Ma S H, Sun Y N, et al. Colla Corii Asini prevents H₂O₂-induced cellular aging and skin barrier damage in HaCaT keratinocytes [J]. J Food Biochem, 2025, 2025(1): 2885165.
Chen L, Wu B F, Mo L, et al. High-content screening identifies ganoderic acid A as a senotherapeutic to prevent cellular senescence and extend healthspan in preclinical models [J]. Nat Commun, 2025, 16:2878.
Armulik A, Genové G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises [J]. Dev Cell, 2011, 21(2): 193-215.
Winkler E A, Bell R D, Zlokovic B V. Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling [J]. Mol Neurodegener, 2010, 5: 32.
Li M, Zhao Y Y, Cui J F. Matrix stiffness in regulation of tumor angiogenesis [J]. World Chin J Digestol, 2022, 30(20): 871-878.
李建斌, 吴锐. 周细胞脱失与神经精神性狼疮血瘀证目征和血脑屏障功能障碍的相关性[J]. 实用医学杂志, 2025, 41(6): 790-799.
朱姗, 赵志月, 王子静, 等. 皮肤老化分子机制及中药防治皮肤老化研究进展[J]. 天津中医药大学学报, 2021, 40(4): 431-439.
程浩然, 梁颢, 陈求芳, 等. 智能响应型水凝胶在皮肤光老化修复中的研究进展[J].中草药, 2026, 57(4): 1528-1537.
Quan T, Fisher G J. Role of age-associated alterations of the dermal extracellular matrix microenvironment in human skin aging: A mini-review [J]. Gerontology, 2015, 61(5): 427-434.
Franceschi C, Garagnani P, Parini P, et al. Inflammaging: A new immune-metabolic viewpoint for age-related diseases [J]. Nat Rev Endocrinol, 2018, 14(10): 576-590.
Augustin H G, Koh G Y, Thurston G, et al. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system [J]. Nat Rev Mol Cell Biol, 2009, 10(3): 165-177.
Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-Tie pathway [J]. Nat Rev Drug Discov, 2017, 16(9): 635-661.
王平. 中医药干预肺血管衰老的研究进展与展望[J]. 老年医学与保健, 2020, 26(6): 904-907.
Sha L L, Zhao Y M, Li S Y, et al. Insights to Ang/Tie signaling pathway: Another rosy dawn for treating retinal and choroidal vascular diseases [J]. J Transl Med, 2024, 22(1): 898.
Zhang Y, Lin S, Liu J, et al. Ang1/Tie2/VE-cadherin signaling regulates DPSCs in vascular maturation [J]. J Dent Res, 2024, 103(1):101-110.
Sun Y, Wang X, Liu T W, et al. The multifaceted role of the SASP in atherosclerosis: From mechanisms to therapeutic opportunities [J]. Cell Biosci, 2022, 12(1): 74.
Han Y, Kim S Y. Endothelial senescence in vascular diseases: Current understanding and future opportunities in senotherapeutics [J]. Exp Mol Med, 2023, 55(1): 1-12.
Guida S, Ciardo S, Galadari H, et al. Correlating optical coherence tomography and other noninvasive imaging features with atrophic and hypertrophic skin photoaging [J]. Int J Dermatol, 2025, 64(8):1441-1445.
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2026年第57卷第16期

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doi: 10.7501/j.issn.0253-2670.2026.16.013

接收时间：2026-02-02
首发时间：2026-10-22
出版时间：2026-08-28

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收稿日期：2026-02-02

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山东东阿阿胶股份有限公司研究基金资助项目

中国中医科学院科技创新工程创新能力提升专项

中央级公益性科研院所基本科研业务费专项

泰山工业专项

中央引导地方科技发展资金

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^1.中国中医科学院医学实验中心, 北京 100700

^2.沈阳药科大学中药学院, 辽宁沈阳 110016

^3.东阿阿胶股份有限公司国家胶类中药工程技术研究中心, 山东聊城 252200

^4.中国中医科学院医学实验中心, 北京 100700

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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