BMP9对动脉性肺动脉高压肺血管内皮细胞影响的研究进展
Research Progress on the Effect of BMP9 on Pulmonary Vascular Endothelial Cells in Pulmonary Arterial Hypertension
摘要: 动脉性肺动脉高压(Pulmonary Arterial Hypertension, PAH),即第1大类肺动脉高压,是一种以高发病率和死亡率为特点的血管疾病,其主要表现是肺血管重塑和肺血管阻力增加,最终导致右心室衰竭甚至死亡。骨形态发生蛋白9 (Bone Morphogenetic Protein 9, BMP9)属于转化生长因子β (Transforming Growth Factor-β, TGF-β)家族,主要由肝脏星状细胞产生,随血液循环到肺血管内皮细胞上与受体结合,在PAH中发挥相应的生物学效应,但是部分研究结果是相互矛盾的。本文对PAH中BMP9的信号通路及BMP9对肺血管内皮细胞作用的研究和进展进行综述。
Abstract: Arterial pulmonary hypertension (PAH), also known as the group 1 pulmonary hypertension, is a vascular disease characterized by high morbidity and mortality, and its main manifestations are pulmonary vascular remodeling and increased pulmonary vascular resistance, which eventually leads to right ventricular failure and even death. Bone Morphogenetic Protein 9 (BMP9) belongs to the Transforming Growth Factor-β (TGF-β) family, which is mainly produced by hepatic stellate cells, which circulates to pulmonary vascular endothelial cells with blood and bind to their receptors to exert corresponding biological effects in PAH, but some research results are contradictory. This article briefly reviews the BMP9 signaling pathway in PAH and the research and progress of BMP9 on pulmonary vascular endothelial cells.
文章引用:高婷, 王丽红. BMP9对动脉性肺动脉高压肺血管内皮细胞影响的研究进展[J]. 临床医学进展, 2024, 14(8): 1195-1200. https://doi.org/10.12677/acm.2024.1482340

参考文献

[1] 中华医学会呼吸病学分会肺栓塞与肺血管病学组, 中国医师协会呼吸医师分会肺栓塞与肺血管病工作委员会, 全国肺栓塞与肺血管病防治协作组, 等. 中国肺动脉高压诊断与治疗指南(2021版) [J]. 中华医学杂志, 2021, 101(1): 11-51.
[2] Galiè, N., Humbert, M., Vachiery, J., Gibbs, S., Lang, I., Torbicki, A., et al. (2015) 2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. European Heart Journal, 37, 67-119. [Google Scholar] [CrossRef] [PubMed]
[3] Maron, B.A., Abman, S.H., Elliott, C.G., Frantz, R.P., Hopper, R.K., Horn, E.M., et al. (2021) Pulmonary Arterial Hypertension: Diagnosis, Treatment, and Novel Advances. American Journal of Respiratory and Critical Care Medicine, 203, 1472-1487. [Google Scholar] [CrossRef] [PubMed]
[4] Farber, H.W., Miller, D.P., Poms, A.D., Badesch, D.B., Frost, A.E., Rouzic, E.M., et al. (2015) Five-Year Outcomes of Patients Enrolled in the REVEAL Registry. Chest, 148, 1043-1054. [Google Scholar] [CrossRef] [PubMed]
[5] Hiepen, C., Yadin, D., Rikeit, P., Dörpholz, G. and Knaus, P. (2016) Actions from Head to Toe: An Update on Bone/Body Morphogenetic Proteins in Health and Disease. Cytokine & Growth Factor Reviews, 27, 1-11. [Google Scholar] [CrossRef] [PubMed]
[6] Bidart, M., Ricard, N., Levet, S., Samson, M., Mallet, C., David, L., et al. (2011) BMP9 Is Produced by Hepatocytes and Circulates Mainly in an Active Mature Form Complexed to Its Prodomain. Cellular and Molecular Life Sciences, 69, 313-324. [Google Scholar] [CrossRef] [PubMed]
[7] Bragdon, B., Moseychuk, O., Saldanha, S., King, D., Julian, J. and Nohe, A. (2011) Bone Morphogenetic Proteins: A Critical Review. Cellular Signalling, 23, 609-620. [Google Scholar] [CrossRef] [PubMed]
[8] Breitkopf-Heinlein, K., Meyer, C., König, C., Gaitantzi, H., Addante, A., Thomas, M., et al. (2017) BMP-9 Interferes with Liver Regeneration and Promotes Liver Fibrosis. Gut, 66, 939-954. [Google Scholar] [CrossRef] [PubMed]
[9] David, L., Mallet, C., Keramidas, M., Lamandé, N., Gasc, J., Dupuis-Girod, S., et al. (2008) Bone Morphogenetic Protein-9 Is a Circulating Vascular Quiescence Factor. Circulation Research, 102, 914-922. [Google Scholar] [CrossRef] [PubMed]
[10] Fong, D., Bisson, M., Laberge, G., McManus, S., Grenier, G., Faucheux, N., et al. (2013) Bone Morphogenetic Protein-9 Activates Smad and ERK Pathways and Supports Human Osteoclast Function and Survival in Vitro. Cellular Signalling, 25, 717-728. [Google Scholar] [CrossRef] [PubMed]
[11] Li, Q., Gu, X., Weng, H., Ghafoory, S., Liu, Y., Feng, T., et al. (2013) Bone Morphogenetic Protein‐9 Induces Epithelial to Mesenchymal Transition in Hepatocellular Carcinoma Cells. Cancer Science, 104, 398-408. [Google Scholar] [CrossRef] [PubMed]
[12] 马翠, 王华. BMP9与肝脏疾病的研究进展[J]. 中国药理学通报, 2020, 36(8): 1045-1048.
[13] Wang, J., Weng, Y., Zhang, M., Li, Y., Fan, M., Guo, Y., et al. (2016) BMP9 Inhibits the Growth and Migration of Lung Adenocarcinoma A549 Cells in a Bone Marrow Stromal Cell-Derived Microenvironment through the MAPK/ERK and NF-κB Pathways. Oncology Reports, 36, 410-418. [Google Scholar] [CrossRef] [PubMed]
[14] Xu, D., Zhao, Y., Wang, J., He, J., Weng, Y. and Luo, J. (2012) Smads, p38 and ERK1/2 Are Involved in BMP9-Induced Osteogenic Differentiation of C3H10T1/2 Mesenchymal Stem Cells. BMB Reports, 45, 247-252. [Google Scholar] [CrossRef] [PubMed]
[15] Ruopp, N.F. and Cockrill, B.A. (2022) Diagnosis and Treatment of Pulmonary Arterial Hypertension: A Review. JAMA, 327, 1379-1391. [Google Scholar] [CrossRef] [PubMed]
[16] 吾拉尔∙阿德力, 迪丽努尔∙买买提依明, 麦尔哈巴∙雪热提. 动脉性肺动脉高压危险因素、危险分层工具[J]. 中文科技期刊数据库(全文版)医药卫生, 2023(2): 1-4.
[17] Shah, A.J., Vorla, M. and Kalra, D.K. (2022) Molecular Pathways in Pulmonary Arterial Hypertension. International Journal of Molecular Sciences, 23, Article 10001. [Google Scholar] [CrossRef] [PubMed]
[18] Humbert, M., McLaughlin, V., Gibbs, J.S.R., Gomberg-Maitland, M., Hoeper, M.M., Preston, I.R., et al. (2021) Sotatercept for the Treatment of Pulmonary Arterial Hypertension. New England Journal of Medicine, 384, 1204-1215. [Google Scholar] [CrossRef] [PubMed]
[19] David, L., Mallet, C., Mazerbourg, S., Feige, J. and Bailly, S. (2006) Identification of BMP9 and BMP10 as Functional Activators of the Orphan Activin Receptor-Like Kinase 1 (ALK1) in Endothelial Cells. Blood, 109, 1953-1961. [Google Scholar] [CrossRef] [PubMed]
[20] Wang, X., Lian, T., Jiang, X., Liu, S., Li, S., Jiang, R., et al. (2018) Germline BMP9 Mutation Causes Idiopathic Pulmonary Arterial Hypertension. European Respiratory Journal, 53, Article 1801609. [Google Scholar] [CrossRef] [PubMed]
[21] Long, L., Ormiston, M.L., Yang, X., Southwood, M., Gräf, S., Machado, R.D., et al. (2015) Selective Enhancement of Endothelial BMPR-II with BMP9 Reverses Pulmonary Arterial Hypertension. Nature Medicine, 21, 777-785. [Google Scholar] [CrossRef] [PubMed]
[22] Theilmann, A.L., Hawke, L.G., Hilton, L.R., Whitford, M.K.M., Cole, D.V., Mackeil, J.L., et al. (2020) Endothelial BMPR2 Loss Drives a Proliferative Response to BMP (Bone Morphogenetic Protein) 9 via Prolonged Canonical Signaling. Arteriosclerosis, Thrombosis, and Vascular Biology, 40, 2605-2618. [Google Scholar] [CrossRef] [PubMed]
[23] Al Tarrass, M., Belmudes, L., Koça, D., Azemard, V., Liu, H., Al Tabosh, T., et al. (2024) Large-Scale Phosphoproteomics Reveals Activation of the MAPK/GADD45β/P38 Axis and Cell Cycle Inhibition in Response to BMP9 and BMP10 Stimulation in Endothelial Cells. Cell Communication and Signaling, 22, Article No. 158. [Google Scholar] [CrossRef] [PubMed]
[24] Desroches‐Castan, A., Tillet, E., Bouvard, C. and Bailly, S. (2021) BMP9 and BMP10: Two Close Vascular Quiescence Partners That Stand Out. Developmental Dynamics, 251, 158-177. [Google Scholar] [CrossRef] [PubMed]
[25] Upton, P.D., Park, J.E.S., De Souza, P.M., Davies, R.J., Griffiths, M.J.D., Wort, S.J., et al. (2020) Endothelial Protective Factors BMP9 and BMP10 Inhibit CCL2 Release by Human Vascular Endothelial Cells. Journal of Cell Science, 133, jcs239715. [Google Scholar] [CrossRef] [PubMed]
[26] Ricard, N., Bailly, S., Guignabert, C. and Simons, M. (2021) The Quiescent Endothelium: Signalling Pathways Regulating Organ-Specific Endothelial Normalcy. Nature Reviews Cardiology, 18, 565-580. [Google Scholar] [CrossRef] [PubMed]
[27] Lamouille, S., Xu, J. and Derynck, R. (2014) Molecular Mechanisms of Epithelial-Mesenchymal Transition. Nature Reviews Molecular Cell Biology, 15, 178-196. [Google Scholar] [CrossRef] [PubMed]
[28] Szulcek, R., Sanchez-Duffhues, G., Rol, N., Pan, X., Tsonaka, R., Dickhoff, C., et al. (2020) Exacerbated Inflammatory Signaling Underlies Aberrant Response to BMP9 in Pulmonary Arterial Hypertension Lung Endothelial Cells. Angiogenesis, 23, 699-714. [Google Scholar] [CrossRef] [PubMed]
[29] Reynolds, A.M., Holmes, M.D., Danilov, S.M. and Reynolds, P.N. (2011) Targeted Gene Delivery of BMPR2 Attenuates Pulmonary Hypertension. European Respiratory Journal, 39, 329-343. [Google Scholar] [CrossRef] [PubMed]
[30] Spiekerkoetter, E., Tian, X., Cai, J., Hopper, R.K., Sudheendra, D., Li, C.G., et al. (2013) FK506 Activates BMPR2, Rescues Endothelial Dysfunction, and Reverses Pulmonary Hypertension. Journal of Clinical Investigation, 123, 3600-3613. [Google Scholar] [CrossRef] [PubMed]
[31] Upton, P.D., Davies, R.J., Trembath, R.C. and Morrell, N.W. (2009) Bone Morphogenetic Protein (BMP) and Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-Like Kinase-1 in Human Pulmonary Artery Endothelial Cells. Journal of Biological Chemistry, 284, 15794-15804. [Google Scholar] [CrossRef] [PubMed]
[32] Scharpfenecker, M., van Dinther, M., Liu, Z., van Bezooijen, R.L., Zhao, Q., Pukac, L., et al. (2007) BMP-9 Signals via ALK1 and Inhibits bFGF-Induced Endothelial Cell Proliferation and VEGF-Stimulated Angiogenesis. Journal of Cell Science, 120, 964-972. [Google Scholar] [CrossRef] [PubMed]
[33] Tu, L., Desroches-Castan, A., Mallet, C., Guyon, L., Cumont, A., Phan, C., et al. (2019) Selective BMP-9 Inhibition Partially Protects against Experimental Pulmonary Hypertension. Circulation Research, 124, 846-855. [Google Scholar] [CrossRef] [PubMed]
[34] Bouvard, C., Tu, L., Rossi, M., Desroches-Castan, A., Berrebeh, N., Helfer, E., et al. (2021) Different Cardiovascular and Pulmonary Phenotypes for Single-and Double-Knock-Out Mice Deficient in BMP9 and BMP10. Cardiovascular Research, 118, 1805-1820. [Google Scholar] [CrossRef] [PubMed]
[35] Li, W. and Quigley, K. (2024) Bone Morphogenetic Protein Signalling in Pulmonary Arterial Hypertension: Revisiting the BMPRII Connection. Biochemical Society Transactions, 52, 1515-1528. [Google Scholar] [CrossRef] [PubMed]