中国临床药理学与治疗学 ›› 2026, Vol. 31 ›› Issue (5): 658-665.doi: 10.12092/j.issn.1009-2501.2026.05.010
收稿日期:2025-02-28
修回日期:2025-05-16
出版日期:2026-05-26
发布日期:2026-06-02
通讯作者:
李澜
E-mail:yyk970607@163.com;lilan_0813@163.com
作者简介:杨雅坤,女,博士研究生在读,研究方向:中医药防治心血管疾病的相关研究。E-mail:基金资助:
Yakun YANG(
), Guanwei FAN, Lan LI(
)
Received:2025-02-28
Revised:2025-05-16
Online:2026-05-26
Published:2026-06-02
Contact:
Lan LI
E-mail:yyk970607@163.com;lilan_0813@163.com
摘要:
心脏淋巴管生成在维持组织-液体平衡、免疫反应和脂质吸收中起主要作用,但心脏淋巴重塑受损/过度以及淋巴引流不足与多种心血管疾病的发生有关。本综述重点总结了心脏淋巴管生成的分子调控机制,并剖析其在心血管疾病中的动态作用,也探讨了淋巴-免疫互作机制在心肌组织损伤修复中的影响,以及靶向淋巴管生成在心血管疾病治疗中的潜在价值。淋巴管生成早期可能通过清除代谢废物、减轻水肿促进修复,而慢性期的过度激活或功能障碍则可能加剧纤维化与炎症扩散。因此,深入探究心脏淋巴管生成在心血管疾病中的作用机制,将为开发新的治疗策略提供重要理论依据。
中图分类号:
杨雅坤, 樊官伟, 李澜. 心脏淋巴管生成在心血管疾病中的最新研究进展[J]. 中国临床药理学与治疗学, 2026, 31(5): 658-665.
Yakun YANG, Guanwei FAN, Lan LI. Recent advances of cardiac lymphangiogenesis in cardiovascular disease[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(5): 658-665.
| 疾病类型 | 关键调节因子变化 | 功能影响 |
| 动脉粥样硬化 | VEGF-C/VEGFR-3表达↑,炎症因子激活 | 斑块周围淋巴管生成,斑块内淋巴引流不足导致 脂质积累 |
| 高血压 | VEGF-C↑?,Ang Ⅱ抑制淋巴管生成 | 淋巴管功能不全,加剧心肌间质水肿,长期促进 心肌纤维化 |
| 心肌梗死 | VEGFR-3、PROX1↑(早期);VEGF-C/VEGF-D/ VEGFR-3↓(晚期) | 淋巴管再生减轻水肿,改善修复(早期);晚期过度 生成可能促进纤维化 |
| 非缺血性心肌病 | CCL21、VEGF-C、VEGF-D↑(代偿性) | 淋巴管稀疏导致慢性水肿,心肌僵硬度↑,舒张功 能恶化 |
| 心肌炎 | 炎症因子↑ | 淋巴管功能损伤加重炎症扩散,水肿和免疫细胞 浸润加剧收缩功能障碍 |
| 心力衰竭 | LYVE1、PROX1↓ | 淋巴回流不足导致慢性水肿,纤维化加重,射血分 数进一步下降 |
| 心脏移植 | 排斥反应中VEGFR3↓ | 淋巴管损伤加剧移植心脏水肿,排斥反应中淋巴- 免疫交互促进慢性排斥 |
表 1 心脏淋巴管在不同心血管疾病中的作用总结
Table 1 Summary of the role of cardiac lymphatic vessels in different cardiovascular diseases
| 疾病类型 | 关键调节因子变化 | 功能影响 |
| 动脉粥样硬化 | VEGF-C/VEGFR-3表达↑,炎症因子激活 | 斑块周围淋巴管生成,斑块内淋巴引流不足导致 脂质积累 |
| 高血压 | VEGF-C↑?,Ang Ⅱ抑制淋巴管生成 | 淋巴管功能不全,加剧心肌间质水肿,长期促进 心肌纤维化 |
| 心肌梗死 | VEGFR-3、PROX1↑(早期);VEGF-C/VEGF-D/ VEGFR-3↓(晚期) | 淋巴管再生减轻水肿,改善修复(早期);晚期过度 生成可能促进纤维化 |
| 非缺血性心肌病 | CCL21、VEGF-C、VEGF-D↑(代偿性) | 淋巴管稀疏导致慢性水肿,心肌僵硬度↑,舒张功 能恶化 |
| 心肌炎 | 炎症因子↑ | 淋巴管功能损伤加重炎症扩散,水肿和免疫细胞 浸润加剧收缩功能障碍 |
| 心力衰竭 | LYVE1、PROX1↓ | 淋巴回流不足导致慢性水肿,纤维化加重,射血分 数进一步下降 |
| 心脏移植 | 排斥反应中VEGFR3↓ | 淋巴管损伤加剧移植心脏水肿,排斥反应中淋巴- 免疫交互促进慢性排斥 |
| 1 | Roth GA, Mensah GA, Johnson CO, et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: Update from the GBD 2019 study[J]. J Am Coll Cardiol, 2020, 76 (25): 2982- 3021. |
| 2 |
Heron C, Dumesnil A, Houssari M, et al. Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure[J]. Cardiovasc Res, 2023, 119 (2): 492- 505.
doi: 10.1093/cvr/cvac086 |
| 3 |
Bai Y, Chen L, Guo F, et al. EphrinB2-mediated CDK5/ISL1 pathway enhances cardiac lymphangiogenesis and alleviates ischemic injury by resolving post-MI inflammation[J]. Signal Transduct Target Ther, 2024, 9 (1): 326.
doi: 10.1038/s41392-024-02019-4 |
| 4 |
Brakenhielm E, Alitalo K. Cardiac lymphatics in health and disease[J]. Nat Rev Cardiol, 2019, 16 (1): 56- 68.
doi: 10.1038/s41569-018-0087-8 |
| 5 |
Liu X, Oliver G. The Lymphatic vasculature in cardiac development and ischemic heart disease[J]. Circ Res, 2023, 132 (9): 1246- 1253.
doi: 10.1161/CIRCRESAHA.122.321672 |
| 6 |
Flaht-Zabost A, Gula G, Ciszek B, et al. Cardiac mouse lymphatics: developmental and anatomical update[J]. Anat Rec (Hoboken), 2014, 297 (6): 1115- 1130.
doi: 10.1002/ar.22912 |
| 7 |
Cooper STE, Lokman AB, Riley PR. Role of the Lymphatics in crdiac disease[J]. Arterioscler Thromb Vasc Biol, 2024, 44 (6): 1181- 1190.
doi: 10.1161/ATVBAHA.124.319854 |
| 8 |
Dieterich LC, Seidel CD, Detmar M. Lymphatic vessels: new targets for the treatment of inflammatory diseases[J]. Angiogenesis, 2014, 17 (2): 359- 371.
doi: 10.1007/s10456-013-9406-1 |
| 9 |
Matsumoto K, Ema M. Roles of VEGF-A signalling in development, regeneration, and tumours[J]. J Biochem, 2014, 156 (1): 1- 10.
doi: 10.1093/jb/mvu031 |
| 10 |
Klotz L, Norman S, Vieira JM, et al. Cardiac lymphatics are heterogeneous in origin and respond to injury[J]. Nature, 2015, 522 (7554): 62- 67.
doi: 10.1038/nature14483 |
| 11 |
Montenegro-Navarro N, García-Báez C, García-Caballero M. Molecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology[J]. Nat Commun, 2023, 14 (1): 8389.
doi: 10.1038/s41467-023-44133-x |
| 12 |
刘晶晶, 陈昌贵, 孙茹雪, 等. 基于Yes相关蛋白/同源异型盒转录因子通路探讨淋巴管新生在高血压心肌重构中的作用[J]. 实用医学杂志, 2023, 39 (3): 289- 297.
doi: 10.3969/j.issn.1006-5725.2023.03.005 |
| 13 |
Herzog BH, Fu J, Wilson SJ, et al. Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2[J]. Nature, 2013, 502 (7469): 105- 109.
doi: 10.1038/nature12501 |
| 14 |
Sabine A, Bovay E, Demir CS, et al. FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature[J]. J Clin Invest, 2015, 125 (10): 3861- 3877.
doi: 10.1172/JCI80454 |
| 15 |
Fatima A, Wang Y, Uchida Y, et al. Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation[J]. J Clin Invest, 2016, 126 (7): 2437- 2451.
doi: 10.1172/JCI80465 |
| 16 | Brakenhielm E, González A, Díez J. Role of cardiac lymphatics in myocardial edema and fibrosis: JACC review topic of the week[J]. J Am Coll Cardiol, 2020, 76 (6): 735- 744. |
| 17 |
Vachon L, Smaani A, Tessier N, et al. Downregulation of low-density lipoprotein receptor mRNA in lymphatic endothelial cells impairs lymphatic function through changes in intracellular lipids[J]. Theranostics, 2022, 12 (3): 1440- 1458.
doi: 10.7150/thno.58780 |
| 18 |
Yeo KP, Lim HY, Thiam CH, et al. Efficient aortic lymphatic drainage is necessary for atherosclerosis regression induced by ezetimibe[J]. Sci Adv, 2020, 6 (50): eabc2697.
doi: 10.1126/sciadv.abc2697 |
| 19 |
Lin QY, Bai J, Liu JQ, et al. Angiotensin II stimulates the proliferation and migration of lymphatic endothelial cells through angiotensin type 1 receptors[J]. Front Physiol, 2020, 11, 560170.
doi: 10.3389/fphys.2020.560170 |
| 20 |
Cooper STE, Westaby JD, Haines ZHR, et al. Of mouse and man: Cross-species characterization of hypertensive cardiac remodeling[J]. Int J Mol Sci, 2022, 23 (14): 7709.
doi: 10.3390/ijms23147709 |
| 21 |
Yang GH, Zhou X, Ji WJ, et al. VEGF-C-mediated cardiac lymphangiogenesis in high salt intake accelerated progression of left ventricular remodeling in spontaneously hypertensive rats[J]. Clin Exp Hypertens, 2017, 39 (8): 740- 747.
doi: 10.1080/10641963.2017.1324478 |
| 22 |
Pal S, Bagchi AK, Henry DS, et al. Rhythmic contractions of lymph vessels and lymph flow are disrupted in hypertensive rats[J]. Hypertension, 2025, 82 (1): 72- 83.
doi: 10.1161/HYPERTENSIONAHA.124.23194 |
| 23 |
Gancz D, Perlmoter G, Yaniv K. Formation and growth of cardiac lymphatics during embryonic development, heart regeneration, and disease[J]. Cold Spring Harb Perspect Biol, 2020, 12 (6): a037176.
doi: 10.1101/cshperspect.a037176 |
| 24 |
Kholová I, Dragneva G, Cermáková P, et al. Lymphatic vasculature is increased in heart valves, ischaemic and inflamed hearts and in cholesterol-rich and calcified atherosclerotic lesions[J]. Eur J Clin Invest, 2011, 41 (5): 487- 497.
doi: 10.1111/j.1365-2362.2010.02431.x |
| 25 |
Vieira JM, Norman S, Villa Del Campo C, et al. The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction[J]. J Clin Invest, 2018, 128 (8): 3402- 3412.
doi: 10.1172/JCI97192 |
| 26 |
Keller TCS 4th, Lim L, Shewale SV, et al. Genetic blockade of lymphangiogenesis does not impair cardiac function after myocardial infarction[J]. J Clin Invest, 2021, 131 (20): e147070.
doi: 10.1172/JCI147070 |
| 27 |
Balint L, Patel S, Serafin DS, et al. Lymphatic activation of ACKR3 signaling regulates lymphatic response after ischemic heart injury[J]. Arterioscler Thromb Vasc Biol, 2025, 45 (5): 754- 768.
doi: 10.1161/ATVBAHA.124.322288 |
| 28 |
Pu Z, Shimizu Y, Hayashi T, et al. Cardiac lymphatic insufficiency leads to diastolic dysfunction via myocardial morphologic change[J]. JACC Basic Transl Sci, 2023, 8 (8): 958- 972.
doi: 10.1016/j.jacbts.2023.01.008 |
| 29 | Chen YL, Lin YN, Xu J, et al. Macrophage-derived VEGF-C reduces cardiac inflammation and prevents heart dysfunction in CVB3-induced viral myocarditis via remodeling cardiac lymphatic vessels [J]. Int Immunopharmacol, 2024, 143(Pt 1): 113377. |
| 30 |
Niinimäki E, Mennander AA, Paavonen T, et al. Lymphangiogenesis is increased in heart valve endocarditis[J]. Int J Cardiol, 2016, 219, 317- 321.
doi: 10.1016/j.ijcard.2016.06.049 |
| 31 |
Dashkevich A, Bloch W, Antonyan A, et al. Morphological and quantitative changes of the initial myocardial lymphatics in terminal heart failure[J]. Lymphat Res Biol, 2009, 7 (1): 21- 27.
doi: 10.1089/lrb.2008.1010 |
| 32 | Rossitto G, Mary S, McAllister C, et al. Reduced lymphatic reserve in heart failure with preserved ejection fraction[J]. J Am Coll Cardiol, 2020, 76 (24): 2817- 2829. |
| 33 |
Guo X, Huang C, Zhang L, et al. Lymphatic endothelial branched-chain amino acid catabolic defects undermine cardiac lymphatic integrity and drive HFpEF[J]. Circulation, 2025, 141 (13): 1099- 1115.
doi: 10.1161/circulationaha.124.071741 |
| 34 |
Gong H, Wang T, Sun X, et al. Fibroblasts facilitate lymphatic vessel formation in transplanted heart[J]. Theranostics, 2024, 14 (5): 1886- 1908.
doi: 10.7150/thno.92103 |
| 35 |
Bizou M, Itier R, Majdoubi M, et al. Cardiac macrophage subsets differentially regulate lymphatic network remodeling during pressure overload[J]. Sci Rep, 2021, 11 (1): 16801.
doi: 10.1038/s41598-021-95723-y |
| 36 |
Glinton KE, Ma W, Lantz C, et al. Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation[J]. J Clin Invest, 2022, 132 (9): e140685.
doi: 10.1172/JCI140685 |
| 37 |
Henri O, Pouehe C, Houssari M, et al. Selective stimulation of cardiac lymphangiogenesis reduces myocardial edema and fibrosis leading to improved cardiac function following myocardial infarction[J]. Circulation, 2016, 133 (15): 1484- 1497.
doi: 10.1161/CIRCULATIONAHA.115.020143 |
| 38 | Cueni LN, Detmar M. The lymphatic system in health and disease[J]. Lymphat Res Biol, 2008, 6 (3/4): 109- 122. |
| 39 | Lin QY, Zhang YL, Bai J, et al. VEGF-C/VEGFR-3 axis protects against pressure-overload induced cardiac dysfunction through regulation of lymphangiogenesis[J]. Clin Transl Med, 2021, 11 (3): e374. |
| 40 |
Leikas AJ, Hartikainen JEK, Kastrup J, et al. Clinical development and proof of principle testing of new regenerative vascular endothelial growth factor-D therapy for refractory angina: rationale and design of the phase 2 ReGenHeart trial[J]. Open Heart, 2024, 11 (2): e002817.
doi: 10.1136/openhrt-2024-002817 |
| 41 |
Leikas AJ, Hassinen I, Hedman A, et al. Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study[J]. Gene Ther, 2022, 29 (5): 289- 293.
doi: 10.1038/s41434-021-00295-1 |
| 42 |
Wang YC, Zhu Y, Meng WT, et al. Dihydrotanshinone I improves cardiac function by promoting lymphangiogenesis after myocardial ischemia-reperfusion injury[J]. Eur J Pharmacol, 2025, 989, 177245.
doi: 10.1016/j.ejphar.2024.177245 |
| 43 | 张迎雪, 朱思楠, 房志锐, 等. 冠心宁注射液促进淋巴管新生改善心肌缺血损伤作用的研究[J]. 中国循证心血管医学杂志, 2025, 17 (2): 175- 179. |
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