犬黏液瘤性二尖瓣疾病的病理机制及治疗研究进展

doi:10.16431/j.cnki.1671-7236.2026.01.010

摘要/Abstract

摘要：

犬黏液瘤性二尖瓣疾病（MMVD）是家犬最常见的心脏病，也是家犬中最常见的心源性死亡原因。二尖瓣的黏液瘤变性主要是其细胞组织学的病变，最主要病变是瓣膜细胞外基质（ECM）的沉积与变性，瓣膜间质细胞（VICs）活化成肌成纤维细胞表型是ECM病变的源头，而VICs的活化有多种机制，包括许多信号分子。在MMVD发病过程中，5-羟色胺（5-HT）通路与瓣膜的物理和化学环境变化有关；转化生长因子-β（TGF-β）通路是控制MMVD发病机制的主要信号通路，且与动物机体内的炎症、机械力和血管紧张素等有关；骨形态发生蛋白（BMP）与动物机体的发育过程有关；活性氧（ROS）参与心肌重塑和心脏衰竭，且能放大TGF-β对MMVD的激活作用；含Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶（ADAMTS）与瓣膜的结构与功能有关。现阶段已出现MMVD颉颃通路药物的治疗，5-HT受体颉颃剂可减轻VICs的活化和MMVD相关的瓣膜组织的病变，细胞膜修复蛋白MG53、成纤维细胞生长因子等细胞因子可抑制TGF-β信号通路从而治疗MMVD。笔者从MMVD的组织病理学、VICs激活机制及MMVD颉颃通路治疗药物的研究进展三大方面进行论述，以期为该疾病的深入研究和临床治疗提供参考。

关键词: 犬; 黏液瘤性二尖瓣疾病; 瓣膜间质细胞; 信号通路

Abstract:

Canine myxomatous mitral valve disease （MMVD） is the most common heart disease and the most common cause of cardiac death in domestic dogs. Myxomatous degeneration of the mitral valve cannot be separated from the histological lesions of mitral valve cells. The most predominant lesion is deposition and degeneration of the extracellular matrix （ECM） of the valve. Activation of valve interstitial cells （VICs） into a myofibroblast phenotype is the source of the ECM lesion. There are multiple mechanisms for the activation of VICs. In the pathogenesis of MMVD， 5-hydroxytryptamine （5-HT） pathway is associated with changes in the physical and chemical environments of valves. The transforming growth factor-β （TGF-β） pathway is the main signalling pathway controlling the pathogenesis of MMVD and is associated with inflammation， mechanical forces and angiotensin in the animal organism. Bone morphogenetic proteins （BMPs） are associated with the developmental process of the animal organism. Reactive oxygen species （ROS） are involved in myocardial remodelling and heart failure and amplify the activation of MMVD by TGF-β， and a disintegrin and metalloproteinase thrombospondin motifs （ADAMTS） are associated with valve structure and function. At this stage， the treatment of MMVD antagonistic pathway drugs has emerged. 5-HT receptor antagonists attenuate VICs activation and MMVD-associated valve tissue lesions， and cytokines such as the cell membrane repair protein MG53 and fibroblast growth factor inhibit the TGF-β signalling pathway thereby treating MMVD. This article discusses three major aspects of MMVD histopathology， the mechanism of VICs activation， and the progress of research on therapeutic drugs for MMVD antagonistic pathways， in order to provide reference for in-depth research and clinical treatment of this disease.

Key words: canine; myxomatous mitral valve disease; valvular interstitial cells; signaling pathways

中图分类号:

S858.292

阮千华, 林佳燕, 林诗琪, 赵津, 刘传敦, 李英, 张辉, 张媛. 犬黏液瘤性二尖瓣疾病的病理机制及治疗研究进展[J]. 中国畜牧兽医, 2026, 53(1): 107-118.

RUAN Qianhua, LIN Jiayan, LIN Shiqi, ZHAO Jin, LIU Chuandun, LI Ying, ZHANG Hui, ZHANG Yuan. Advances in Pathological Mechanisms and Treatment of Canine Myxomatous Mitral Valve Disease[J]. China Animal Husbandry & Veterinary Medicine, 2026, 53(1): 107-118.

图/表 4

参考文献 96

[1]	KEENE B W， ATKINS C E， BONAGURA J D， et al. ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs［J］. Journal of Veterinary Internal Medicine， 2019，33（3）：1127-1140.
[2]	ADLER E， TIDHOLM A. Prevalence of mitral valve regurgitation in 102 asymptomatic Chinese Crested dogs［J］. Journal of Veterinary Cardiology， 2023，46：55-61.
[3]	陈淑敏，曾丽薇，陈宇，等.犬心脏二尖瓣退行性疾病研究进展［J］. 中国畜牧兽医， 2024，51（7）：3215-3223.
	CHEN S M， ZENG L W， CHEN Y， et al. Research progress on mitral degenerative disease of dogs［J］. China Animal Husbandry & Veterinary Medicine， 2024，51（7）：3215-3223. （in Chinese）
[4]	FISHBEIN G A， FISHBEIN M C. Mitral valve pathology［J］. Current Cardiology Reports， 2019，21（7）：61.
[5]	MARECHAUX S， ILLMAN J E， HUYNH J， et al. Functional anatomy and pathophysiologic principles in mitral regurgitation： Non-invasive assessment［J］. Progress in Cardiovascular Disease， 2017，60（3）：289-304.
[6]	PRESUME J， PAIVA M S， GUERREIRO S， et al. Parameters of the mitral apparatus in patients with ischemic and nonischemic dilated cardiomyopathy［J］. The Journal of International Medical Research， 2023，51（12）： 3000605231218645.
[7]	O’BRIEN M J， BEIJERINK N J， WADE C M. Genetics of canine myxomatous mitral valve disease［J］. Animal Genetics， 2021，52（4）：409-421.
[8]	REIMANN M J， CREMER S， CHRISTIANSEN L， et al. Mitral valve transcriptome analysis in thirty-four age-matched Cavalier King Charles Spaniels with or without congestive heart failure caused by myxomatous mitral valve disease［J］. Mammalian Genome， 2024，35（1）：77-89.
[9]	DELWARDE C， CAPOULADE R， MÉROT J， et al. Genetics and pathophysiology of mitral valve prolapse［J］. Frontiers in Cardiovascular Medicine， 2023，10：1077788.
[10]	OYAMA M A， ELLIOTT C， LOUGHRAN K A， et al. Comparative pathology of human and canine myxomatous mitral valve degeneration： 5-HT and TGF-beta mechanisms［J］. Cardiovascular Pathology， 2020，46：107196.
[11]	PAGNOZZI L A， BUTCHER J T. Mechanotransduction mechanisms in mitral valve physiology and disease pathogenesis［J］. Frontiers in Cardiovascular Medicine， 2017，4：83.
[12]	AYOUB S， FERRARI G， GORMAN R C， et al. Heart valve biomechanics and underlying mechanobiology［J］. Comprehensive Physiology， 2016，6（4）：1743-1780.
[13]	AUPPERLE H， MÄRZ I， THIELEBEIN J， et al. Immunohistochemical characterization of the extracellular matrix in normal mitral valves and in chronic valve disease （endocardiosis） in dogs［J］. Research in Veterinary Science， 2009，87（2）：277-283.
[14]	AIKAWA E， BLASER M C， SINGH S A， et al. Challenges and opportunities in valvular heart disease： From molecular mechanisms to the community［J］. Arteriosclerosis， Thrombosis， and Vascular Biology， 2024，44（4）：763-767.
[15]	CULSHAW G J， FRENCH A T， HAN R I， et al. Evaluation of innervation of the mitral valves and the effects of myxomatous degeneration in dogs［J］. American Journal of Veterinary Research， 2010，71（2）：194-202.
[16]	HULIN A， DEROANNE C， LAMBERT C， et al. Emerging pathogenic mechanisms in human myxomatous mitral valve： Lessons from past and novel data［J］. Cardiovascular Pathology， 2013，22（4）：245-250.
[17]	LIU M， FLANAGAN T C， LU C， et al. Culture and characterisation of canine mitral valve interstitial and endothelial cells［J］. Veterinary Journal （London， England： 1997）， 2015，204（1）：32-39.
[18]	RUTKOVSKIY A， MALASHICHEVA A， SULLIVAN G， et al. Valve interstitial cells： The key to understanding the pathophysiology of heart valve calcification［J］. Journal of the American Heart Association， 2017，6（9）： e006339.
[19]	HOWSMON D P， SACKS M S. On valve interstitial cell signaling： The link between multiscale mechanics and mechanobiology［J］. Cardiovascular Engineering and Technology， 2021，12（1）：15-27.
[20]	KHANG A， MEYER K， SACKS M S. An inverse modeling approach to estimate three-dimensional aortic valve interstitial cell stress fiber force levels［J］. Journal of Biomechanical Engineering， 2023，145（12）：31.
[21]	LIU A C， JOAG V R， GOTLIEB A I. The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology［J］. The American Journal of Pathology， 2007，171（5）：1407-1418.
[22]	BLACK A， FRENCH A T， DUKES-MCEWAN J， et al. Ultrastructural morphologic evaluation of the phenotype of valvular interstitial cells in dogs with myxomatous degeneration of the mitral valve［J］. American Journal of Veterinary Research， 2005，66（8）：1408-1414.
[23]	RABKIN-AIKAWA E， FARBER M， AIKAWA M， et al. Dynamic and reversible changes of interstitial cell phenotype during remodeling of cardiac valves［J］. The Journal of Heart Valve Disease， 2004，13（5）：841-847.
[24]	ELEID M F， NKOMO V T， PISLARU S V， et al. Valvular heart disease： New concepts in pathophysiology and therapeutic approaches［J］. Annual Review of Medicine， 2023，74：155-170.
[25]	BARNES N M， AHERN G P， BECAMEL C， et al. International union of basic and clinical pharmacology. cx. classification of receptors for 5-hydroxytryptamine； Pharmacology and function［J］. Pharmacological Reviews， 2021，73（1）：310-520.
[26]	MCCORVY J D， ROTH B L. Structure and function of serotonin G protein-coupled receptors［J］. Pharmacology & Therapeutics， 2015，150：129-142.
[27]	HUTCHESON J D， SETOLA V， ROTH B L， et al. Serotonin receptors and heart valve disease—It was meant 2B［J］. Pharmacology & Therapeutics， 2011，132（2）：146-157.
[28]	CASTILLERO E， FITZPATRICK E， KEENEY S J， et al. Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation［J］. Science Translational Medicine， 2023，15（677）：eadc9606.
[29]	BALACHANDRAN K， HUSSAIN S， YAP C， et al. Elevated cyclic stretch and serotonin result in altered aortic valve remodeling via a mechanosensitive 5-HT（2A） receptor-dependent pathway［J］. Cardiovascular Pathology， 2012，21（3）：206-213.
[30]	WALDUM H， WAHBA A. Serotonin—A driver of progressive heart valve disease［J］. Frontiers in Cardiovascular Medicine， 2022，9：774573.
[31]	LACERDA C M R， MACLEA H B， KISIDAY J D， et al. Static and cyclic tensile strain induce myxomatous effector proteins and serotonin in canine mitral valves［J］. Journal of Veterinary Cardiology， 2012，14（1）：223-230.
[32]	DISATIAN S， LACERDA C， ORTON E C. Tryptophan hydroxylase 1 expression is increased in phenotype-altered canine and human degenerative myxomatous mitral valves［J］. The Journal of Heart Valve Disease， 2010，19（1）：71-78.
[33]	DISATIAN S， ORTON E C. Autocrine serotonin and transforming growth factor beta 1 signaling mediates spontaneous myxomatous mitral valve disease［J］. The Journal of Heart Valve Disease， 2009，18（1）：44-51.
[34]	CREMER S E， SINGLETARY G E， OLSEN L H， et al. Serotonin concentrations in platelets， plasma， mitral valve leaflet， and left ventricular myocardial tissue in dogs with myxomatous mitral valve disease［J］. Journal of Veterinary Internal Medicine， 2014，28（5）：1534-1540.
[35]	DROOGMANS S， ROOSENS B， COSYNS B， et al. Dose dependency and reversibility of serotonin-induced valvular heart disease in rats［J］. Cardiovascular Toxicology， 2009， 9（3）： 134-141.
[36]	BHATTACHARYYA S， JAGROOP A， GUJRAL D M， et al. Circulating plasma and platelet 5-hydroxytryptamine in carcinoid heart disease： A pilot study［J］. The Journal of Heart Valve Disease， 2013，22（3）：400-407.
[37]	ROTHMAN R B， BAUMANN M H. Serotonergic drugs and valvular heart disease［J］. Expert Opinion on Drug Safety， 2009，8（3）：317-329.
[38]	CONNOLLY J M， BAKAY M A， FULMER J T， et al. Fenfluramine disrupts the mitral valve interstitial cell response to serotonin［J］. The American Journal of Pathology， 2009，175（3）：988-997.
[39]	DRIESBAUGH K H， BRANCHETTI E， GRAU J B， et al. Serotonin receptor 2B signaling with interstitial cell activation and leaflet remodeling in degenerative mitral regurgitation［J］. Journal of Molecular and Cellular Cardiology， 2018，115：94-103.
[40]	PAVONE L M， NORRIS R A. Distinct signaling pathways activated by "extracellular" and "intracellular" serotonin in heart valve development and disease［J］. Cell Biochemistry and Biophysics， 2013，67（3）：819-828.
[41]	SCRUGGS S M， DISATIAN S， ORTON E C. Serotonin transmembrane transporter is down-regulated in late-stage canine degenerative mitral valve disease［J］. Journal of Veterinary Cardiology， 2010，12（3）：163-169.
[42]	MARKBY G R， MACRAE V E， SUMMERS K M， et al. Disease severity-associated gene expression in canine myxomatous mitral valve disease is dominated by TGFβ signaling［J］. Frontiers in Genetics， 2020，11：372.
[43]	WU J， JACKSON-WEAVER O， XU J. The TGFβ superfamily in cardiac dysfunction［J］. Acta Biochimica et Biophysica Sinica， 2018，50（4）：323-335.
[44]	MCNAIR A J， MARKBY G R， TANG Q， et al. TGF-β phospho antibody array identifies altered SMAD2， PI3K/AKT/SMAD， and RAC signaling contribute to the pathogenesis of myxomatous mitral valve disease［J］. Frontiers in Veterinary Science， 2023，10：1202001.
[45]	TANG Q， MARKBY G R， MACNAIR A J， et al. TGF-β-induced PI3K/AKT/mTOR pathway controls myofibroblast differentiation and secretory phenotype of valvular interstitial cells through the modulation of cellular senescence in a naturally occurring in vitro canine model of myxomatous mitral valve disease［J］. Cell Proliferation， 2023，56（6）：e13435.
[46]	TANG Q， MCNAIR A J， PHADWAL K， et al. The role of transforming growth factor-β signaling in myxomatous mitral valve degeneration［J］. Frontiers in Cardiovascular Medicine， 2022， 9： 872288.
[47]	ROBERTSON I B， HORIGUCHI M， ZILBERBERG L， et al. Latent TGF-β-binding proteins［J］. Matrix Biology， 2015，47：44-53.
[48]	CALAFIORE A M， TOTARO A， TESTA N， et al. The secret life of the mitral valve［J］. Journal of Cardiac Surgery， 2021，36（1）：247-259.
[49]	LIU A C， GOTLIEB A I. Transforming growth factor-beta regulates in vitro heart valve repair by activated valve interstitial cells［J］. The American Journal of Pathology， 2008，173（5）：1275-1285.
[50]	ROSENKRANZ S. TGF-beta1 and angiotensin networking in cardiac remodeling［J］. Cardiovascular Research， 2004，63（3）：423-432.
[51]	GEIRSSON A， SINGH M， ALI R， et al. Modulation of transforming growth factor-β signaling and extracellular matrix production in myxomatous mitral valves by angiotensin Ⅱ receptor blockers［J］. Circulation， 2012，126（11 ）：S189-S197.
[52]	RIZZO S， BASSO C， LAZZARINI E， et al. TGF-beta1 pathway activation and adherens junction molecular pattern in nonsyndromic mitral valve prolapse［J］. Cardiovascular Pathology， 2015，24（6）：359-367.
[53]	DISHA K， SCHULZ S， KUNTZE T， et al. Transforming growth factor beta-2 mutations in Barlow’s disease and aortic dilatation［J］. The Annals of Thoracic Surgery， 2017， 104（1）：e19-e21.
[54]	HULIN A， DEROANNE C F， LAMBERT C A， et al. Metallothionein-dependent up-regulation of TGF-β2 participates in the remodelling of the myxomatous mitral valve［J］. Cardiovascular Research， 2012，93（3）：480-489.
[55]	CAPON S J， URIBE V， DOMINADO N， et al. Endocardial identity is established during early somitogenesis by BMP signalling acting upstream of npas4l and etv2［J］. Development （Cambridge， England）， 2022，149（9）： dev190421.
[56]	JIAO K， KULESSA H， TOMPKINS K， et al. An essential role of Bmp4 in the atrioventricular septation of the mouse heart［J］. Genes & Development， 2003，17（19）：2362-2367.
[57]	MORRELL N W， BLOCH D B， DIJKE P TEN， et al. Targeting BMP signalling in cardiovascular disease and anaemia［J］. Nature Reviews. Cardiology， 2016，13（2）：106-120.
[58]	HE J， WANG K， WANG B， et al. Effect of the TGF-β/BMP signaling pathway on the proliferation of yak pulmonary artery smooth muscle cells under hypoxic conditions［J］. Animals， 2024，14（14）：2072.
[59]	SAINGER R， GRAU J B， BRANCHETTI E， et al. Human myxomatous mitral valve prolapse： Role of bone morphogenetic protein 4 in valvular interstitial cell activation［J］. Journal of Cellular Physiology， 2012，227（6）：2595-2604.
[60]	DRONKERS E， WAUTERS M M M， GOUMANS M J， et al. Epicardial TGFβ and BMP signaling in cardiac regeneration： What lesson can we learn from the developing heart？［J］. Biomolecules， 2020，10（3）：404.
[61]	LUO J， ZHANG Y， WANG L， et al. Regulators and effectors of bone morphogenetic protein signalling in the cardiovascular system［J］. The Journal of Physiology， 2015，593（14）：2995-3011.
[62]	SUGI Y， YAMAMURA H， OKAGAWA H， et al. Bone morphogenetic protein-2 can mediate myocardial regulation of atrioventricular cushion mesenchymal cell formation in mice［J］. Developmental Biology， 2004，269（2）：505-518.
[63]	JACKSON L F， QIU T H， SUNNARBORG S W， et al. Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling［J］. The EMBO Journal， 2003，22（11）：2704-2716.
[64]	PRAKASH S， BORREGUERO L J J， SYLVA M， et al. Deletion of Fstl1 （Follistatin-Like 1） from the endocardial/endothelial lineage causes mitral valve disease［J］. Arteriosclerosis， Thrombosis， and Vascular Biology， 2017，37（9）：e116-e130.
[65]	THALJI N M， HAGLER M A， ZHANG H， et al. Nonbiased molecular screening identifies novel molecular regulators of fibrogenic and proliferative signaling in myxomatous mitral valve disease［J］. Circulation. Cardiovascular Genetics， 2015，8（3）：516-528.
[66]	DHALLA N S， SHAH A K， ADAMEOVA A， et al. Role of oxidative stress in cardiac dysfunction and subcellular defects due to ischemia-reperfusion injury［J］. Biomedicines， 2022，10（7）：1473.
[67]	LIU W， WANG Y， QIU Z， et al. CircHIPK3 regulates cardiac fibroblast proliferation， migration and phenotypic switching through the miR-152-3p/TGF-β2 axis under hypoxia［J］. PeerJ， 2020，8：e9796.
[68]	SIWIK D A， PAGANO P J， COLUCCI W S. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts［J］. American Journal of Physiology. Cell Physiology， 2001，280（1）：C53-C60.
[69]	LIU Y， HUANG H， XIA W， et al. NADPH oxidase inhibition ameliorates cardiac dysfunction in rabbits with heart failure［J］. Molecular and Cellular Biochemistry， 2010，343（1-2）：143-153.
[70]	LI P F， DIETZ R， VON HARSDORF R. Superoxide induces apoptosis in cardiomyocytes， but proliferation and expression of transforming growth factor-beta1 in cardiac fibroblasts［J］. FEBS Letters， 1999，448（2-3）：206-210.
[71]	HAGLER M A， HADLEY T M， ZHANG H， et al. TGF-β signalling and reactive oxygen species drive fibrosis and matrix remodelling in myxomatous mitral valves［J］. Cardiovascular Research， 2013，99（1）：175-184.
[72]	BONDI C D， MANICKAM N， LEE D Y， et al. NAD（P）H oxidase mediates TGF-beta1-induced activation of kidney myofibroblasts［J］. Journal of the American Society of Nephrology， 2010，21（1）：93-102.
[73]	KALUDERCIC N， CARPI A， MENABÒ R， et al. Monoamine oxidases （MAO） in the pathogenesis of heart failure and ischemia/reperfusion injury［J］. Biochimica et Biophysica Acta， 2011，1813（7）：1323-1332.
[74]	WANG M， ZHANG J， WALKER S J， et al. Involvement of NADPH oxidase in age-associated cardiac remodeling［J］. Journal of Molecular and Cellular Cardiology， 2010，48（4）：765-772.
[75]	SABRI A， HUGHIE H H， LUCCHESI P A. Regulation of hypertrophic and apoptotic signaling pathways by reactive oxygen species in cardiac myocytes［J］. Antioxidants & Redox Signaling， 2003，5（6）：731-740.
[76]	LÓPEZ-GIL J F， TÁRRAGA-LÓPEZ P J. Research on diet and human health［J］. International Journal of Environmental Research and Public Health， 2022， 19（11）：6526.
[77]	CHO K I， SAKUMA I， SOHN I S， et al. Inflammatory and metabolic mechanisms underlying the calcific aortic valve disease［J］. Atherosclerosis， 2018，277：60-65.
[78]	DAIBER A， XIA N， STEVEN S， et al. New therapeutic implications of endothelial nitric oxide synthase （eNOS） function/dysfunction in cardiovascular disease［J］. International Journal of Molecular Sciences， 2019，20（1）：187.
[79]	TANASE D M， VALASCIUC E， GOSAV E M， et al. Contribution of oxidative stress （OS） in calcific aortic valve disease （CAVD）： From pathophysiology to therapeutic targets［J］. Cells， 2022，11（17）：2663.
[80]	WERBNER B， TAVAKOLI-ROUZBEHANI O M， FATAHIAN A N， et al. The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease， aging， and heart failure［J］. The Journal of Cardiovascular Aging， 2023，3（1）：9.
[81]	LUO J D， XIE F， ZHANG W W， et al. Simvastatin inhibits noradrenaline-induced hypertrophy of cultured neonatal rat cardiomyocytes［J］. British Journal of Pharmacology， 2001，132（1）：159-164.
[82]	SANTAMARIA S， DE GROOT R. ADAMTS proteases in cardiovascular physiology and disease［J］. Open Biology， 2020，10（12）：200333.
[83]	DUPUIS L E， NELSON E L， HOZIK B， et al. Adamts5^-/- mice exhibit altered aggrecan proteolytic profiles that correlate with ascending aortic anomalies［J］. Arteriosclerosis， Thrombosis， and Vascular Biology， 2019，39（10）：2067-2081.
[84]	LI F， SONG R， AO L， et al. ADAMTS5 deficiency in calcified aortic valves is associated with elevated pro-osteogenic activity in valvular interstitial cells［J］. Arteriosclerosis， Thrombosis， and Vascular Biology， 2017，37（7）：1339-1351.
[85]	WÜNNEMANN F， TA-SHMA A， PREUSS C， et al. Loss of ADAMTS19 causes progressive non-syndromic heart valve disease［J］. Nature Genetics， 2020，52（1）：40-47.
[86]	MASSADEH S， ALHASHEM A， VAN DE LAAR I M B H， et al. ADAMTS19-associated heart valve defects： Novel genetic variants consolidating a recognizable cardiac phenotype［J］. Clinical Genetics， 2020，98（1）：56-63.
[87]	SANTAMARIA S， FEDOROV O， MCCAFFERTY J， et al. Development of a monoclonal anti-ADAMTS-5 antibody that specifically blocks the interaction with LRP1［J］. mAbs， 2017，9（4）：595-602.
[88]	VAN STAVEREN M D B， MUIS E， SZATMÁRI V. Self-reported utilization of international （ACVIM Consensus） guidelines and the latest clinical trial results on the treatment of dogs with various stages of myxomatous mitral valve degeneration： A survey among veterinary practitioners［J］. Animals， 2024，14（5）： 772.
[89]	EL-ANDARI R， KANG J， BOZSO S， et al. Minimally invasive complex neochordal reconstruction for mitral valve regurgitation［J］. JTCVS Techniques， 2024，27：91-95.
[90]	AYME-DIETRICH E， LAWSON R， CÔTÉ F， et al. The role of 5-HT（2B） receptors in mitral valvulopathy： Bone marrow mobilization of endothelial progenitors［J］. British Journal of Pharmacology， 2017，174（22）：4123-4139.
[91]	LACERDA C M R， KISIDAY J， JOHNSON B， et al. Local serotonin mediates cyclic strain-induced phenotype transformation， matrix degradation， and glycosaminoglycan synthesis in cultured sheep mitral valves［J］. American Journal of Physiology. Heart and Circulatory Physiology， 2012，302（10）：H1983-H1990.
[92]	SOSLAU G. Cardiovascular serotonergic system： Evolution， receptors， transporter， and function［J］. Journal of Experimental Zoology. Part A， Ecological and Integrative Physiology， 2022，337（2）：115-127.
[93]	ADESANYA T M A， RUSSELL M， PARK K H， et al. MG 53 protein protects aortic valve interstitial cells from membrane injury and fibrocalcific remodeling［J］. Journal of the American Heart Association， 2019，8（4）：e9960.
[94]	ZHOU J， ZHU J， JIANG L， et al. Interleukin 18 promotes myofibroblast activation of valvular interstitial cells［J］. International Journal of Cardiology， 2016，221：998-1003.
[95]	GONZALEZ RODRIGUEZ A， SCHROEDER M E， WALKER C J， et al. FGF-2 inhibits contractile properties of valvular interstitial cell myofibroblasts encapsulated in 3D MMP-degradable hydrogels［J］. APL Bioengineering， 2018，2（4）：46104.
[96]	LATIF N， QUILLON A， SARATHCHANDRA P， et al. Modulation of human valve interstitial cell phenotype and function using a fibroblast growth factor 2 formulation［J］. PLoS One， 2015，10（6）：e127844.