Animal Models of Pulmonary Arterial Hypertension and Their Application in Drug Research

doi:10.12300/j.issn.1674-5817.2023.048

Abstract

Abstract:

Pulmonary arterial hypertension is a clinical syndrome characterized by pulmonary vascular remodeling causing increased vascular resistance, which will lead to right heart failure and even death if left untreated. The pathogenesis of pulmonary arterial hypertension has not yet been clarified, and clinical treatments have not been effective in improving prognosis or reducing mortality. To investigate the pathogenesis of pulmonary arterial hypertension and to develop and evaluate more effective and safer drug treatments, establishing related animal disease models is very important. This paper outlines the pathological characteristics of pulmonary arterial hypertension and summarizes the various types of animal models of pulmonary arterial hypertension, as well as describes the progress of the application of these models in three therapeutic pathways and related drug research in the past five years, with a view to providing a reference for the selection of animal models of pulmonary arterial hypertension and research applications.

Key words: Pulmonary arterial hypertension, Animal models, Drug evaluation

CLC Number:

R-332

Jiahui YU, Qian GONG, Lenan ZHUANG. Animal Models of Pulmonary Arterial Hypertension and Their Application in Drug Research[J]. Laboratory Animal and Comparative Medicine, 2023, 43(4): 381-397.

Figures/Tables 2

References 103

1	SCHERMULY R T, GHOFRANI H A, WILKINS M R, et al. Mechanisms of disease: pulmonary arterial hypertension[J]. Nat Rev Cardiol, 2011, 8(8):443-455. DOI: 10.1038/nrcardio.2011.87 .
2	HUMBERT M, GUIGNABERT C, BONNET S, et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives[J]. Eur Respir J, 2019, 53(1):1801887. DOI: 10.1183/13993003.01887-2018 .
3	STENMARK K R, MEYRICK B, GALIE N, et al. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure[J]. Am J Physiol Lung Cell Mol Physiol, 2009, 297(6): L1013-L1032. DOI: 10.1152/ajplung.00217.2009 .
4	SOUTHGATE L, MACHADO R D, GRÄF S, et al. Molecular genetic framework underlying pulmonary arterial hyper-tension[J]. Nat Rev Cardiol, 2020, 17(2):85-95. DOI: 10.1038/s41569-019-0242-x .
5	LAU E M T, GIANNOULATOU E, CELERMAJER D S, et al. Epidemiology and treatment of pulmonary arterial hypertension[J]. Nat Rev Cardiol, 2017, 14(10):603-614. DOI: 10.1038/nrcardio.2017.84 .
6	HASSOUN P M. Pulmonary arterial hypertension[J]. N Engl J Med, 2021, 385(25):2361-2376. DOI: 10.1056/NEJMra2000348 .
7	RUOPP N F, COCKRILL B A. Diagnosis and treatment of pulmonary arterial hypertension: a review[J]. JAMA, 2022, 327(14):1379-1391. DOI: 10.1001/jama.2022.4402 .
8	HUETSCH J C, SURESH K, BERNIER M, et al. Update on novel targets and potential treatment avenues in pulmonary hypertension[J]. Am J Physiol Lung Cell Mol Physiol, 2016, 311(5):L811-L831. DOI: 10.1152/ajplung.00302.2016 .
9	SZTUKA K, JASIŃSKA-STROSCHEIN M. Animal models of pulmonary arterial hypertension: a systematic review and meta-analysis of data from 6126 animals[J]. Pharmacol Res, 2017, 125(Pt B):201-214. DOI: 10.1016/j.phrs.2017.08.003 .
10	MAARMAN G, LECOUR S, BUTROUS G, et al. A comprehensive review: the evolution of animal models in pulmonary hypertension research; are we there yet?[J]. Pulm Circ, 2013, 3(4):739-756. DOI: 10.1086/674770 .
11	BISSERIER M, MATHIYALAGAN P, ZHANG S H, et al. Regulation of the methylation and expression levels of the BMPR2 gene by SIN3a as a novel therapeutic mechanism in pulmonary arterial hypertension[J]. Circulation, 2021, 144(1):52-73. DOI: 10.1161/CIRCULATIONAHA.120.047978 .
12	XIAO R, SU Y, FENG T, et al. Monocrotaline induces endothelial injury and pulmonary hypertension by targeting the extracellular calcium-sensing receptor[J]. J Am Heart Assoc, 2017, 6(4):e004865. DOI: 10.1161/JAHA.116.004865 .
13	CHEN D, ZHANG H F, YUAN T Y, et al. Puerarin-V prevents the progression of hypoxia- and monocrotaline-induced pulmonary hypertension in rodent models[J]. Acta Pharmacol Sin, 2022, 43(9):2325-2339. DOI: 10.1038/s41401-022-00865-y .
14	SU H, XU X L, YAN C, et al. LncRNA H19 promotes the proliferation of pulmonary artery smooth muscle cells through AT1R via sponging let-7b in monocrotaline-induced pulmonary arterial hypertension[J]. Respir Res, 2018, 19(1):254. DOI: 10.1186/s12931-018-0956-z .
15	OMURA J, HABBOUT K, SHIMAUCHI T, et al. Identification of long noncoding RNA H19 as a new biomarker and therapeutic target in right ventricular failure in pulmonary arterial hypertension[J]. Circulation, 2020, 142(15):1464-1484. DOI: 10.1161/CIRCULATIONAHA.120.047626 .
16	WU X H, MA J L, DING D, et al. Experimental animal models of pulmonary hypertension: development and challenges[J]. Animal Model Exp Med, 2022, 5(3):207-216. DOI: 10.1002/ame2.12220 .
17	YAMAZATO Y, YAMAZATO M, ISHIDA A, et al. Intratracheal administration of autologous bone marrow-derived cells ameliorates monocrotaline-induced pulmonary vessel remodeling and lung inflammation in rats[J]. Lung, 2018, 196(2):147-155. DOI: 10.1007/s00408-017-0075-5 .
18	CARMAN B L, PREDESCU D N, MACHADO R, et al. Plexiform arteriopathy in rodent models of pulmonary arterial hypertension[J]. Am J Pathol, 2019, 189(6):1133-1144. DOI: 10.1016/j.ajpath.2019.02.005 .
19	DIGNAM J P, SCOTT T E, KEMP-HARPER B K, et al. Animal models of pulmonary hypertension: getting to the heart of the problem[J]. Br J Pharmacol, 2022, 179(5):811-837. DOI: 10.1111/bph.15444 .
20	BOUCHERAT O, AGRAWAL V, LAWRIE A, et al. The latest in animal models of pulmonary hypertension and right ventricular failure[J]. Circ Res, 2022, 130(9):1466-1486. DOI: 10.1161/CIRCRESAHA.121.319971 .
21	RYAN J, BLOCH K, ARCHER S L. Rodent models of pulmonary hypertension: harmonisation with the world health organisation's categorisation of human PH[J]. Int J Clin Pract Suppl, 2011(172):15-34. DOI: 10.1111/j.1742-1241.2011.02710.x .
22	REHMAN J, ARCHER S L. A proposed mitochondrial-metabolic mechanism for initiation and maintenance of pulmonary arterial hypertension in fawn-hooded rats: the Warburg model of pulmonary arterial hypertension[J]. Adv Exp Med Biol, 2010, 661: 171-185. DOI:10.1007/978-1-60761-500-2_11 .
23	ARCHER S L, MARSBOOM G, KIM G H, et al. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target[J]. Circulation, 2010, 121(24):2661-2671. DOI: 10.1161/CIRCULATIONAHA. 109.916098 .
24	PIAO L, SIDHU V K, FANG Y H, et al. FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate[J]. J Mol Med, 2013, 91(3):333-346. DOI: 10.1007/s00109-012-0982-0 .
25	BOUCHERAT O, PETERLINI T, BOURGEOIS A, et al. Mitochondrial HSP90 accumulation promotes vascular remodeling in pulmonary arterial hypertension[J]. Am J Respir Crit Care Med, 2018, 198(1):90-103. DOI: 10.1164/rccm.201708-1751OC .
26	ZHANG M J, FENG Z Y, HUANG R, et al. Characteristics of pulmonary vascular remodeling in a novel model of shunt-associated pulmonary arterial hypertension[J]. Med Sci Monit, 2018, 24:1624-1632. DOI: 10.12659/msm.905654 .
27	WANG L P, GUO L L, ZHU L M, et al. Characteristics of pulmonary vascular remodeling in a porcine model of shunt-associated pulmonary arterial hypertension[J]. Pediatr Cardiol, 2020, 41(4):669-676. DOI: 10.1007/s00246-019-02275-0 .
28	JIANG Y Y, HE G W. Early diagnostic features of left-to-right shunt-induced pulmonary arterial hypertension in piglets[J]. Ann Thorac Surg, 2018, 106(5):1396-1405. DOI: 10.1016/j.athoracsur.2018.05.052 .
29	MENG L K, TENG X, LIU Y, et al. Vital roles of gremlin-1 in pulmonary arterial hypertension induced by systemic-to-pulmonary shunts[J]. J Am Heart Assoc, 2020, 9(15):e016586. DOI: 10.1161/jaha.120.016586 .
30	MENG L K, YUAN W, CHI H J, et al. Genetic deletion of CMG2 exacerbates systemic-to-pulmonary shunt-induced pulmonary arterial hypertension[J]. FASEB J, 2021, 35(4):e21421. DOI: 10.1096/fj.202000299R .
31	WANG K, CHEN C S, MA J F, et al. Contribution of calcium-activated chloride channel to elevated pulmonary artery pressure in pulmonary arterial hypertension induced by high pulmonary blood flow[J]. Int J Clin Exp Pathol, 2015, 8(1):146-154.
32	GARCIA R, DIEBOLD S. Simple, rapid, and effective method of producing aortocaval shunts in the rat[J]. Cardiovasc Res, 1990, 24(5):430-432. DOI: 10.1093/cvr/24.5.430 .
33	SHANG L F, WANG K, LIU D L, et al. TMEM16A regulates the cell cycle of pulmonary artery smooth muscle cells in high-flow-induced pulmonary arterial hypertension rat model[J]. Exp Ther Med, 2020, 19(5):3275-3281. DOI: 10.3892/etm.2020.8589 .
34	LIU D L, WANG K, SU D Y, et al. TMEM16A regulates pulmonary arterial smooth muscle cells proliferation via p38MAPK/ERK pathway in high pulmonary blood flow-induced pulmonary arterial hypertension[J]. J Vasc Res, 2020, 58(1):27-37. DOI: 10.1159/000511267 .
35	LIU X Y, MENG L K, YUAN W, et al. Evidence for ANTXR2 as a therapeutic target on systemic-to-pulmonary shunt induced pulmonary arterial hypertension[J]. Eur Heart J, 2019, 40 ():ehz746.0733. DOI: 10.1093/eurheartj/ehz746.0733 .
36	GUAN H, YANG X F, SHI T, et al. CTRP9 mitigates the progression of arteriovenous shunt-induced pulmonary artery hypertension in rats[J]. Cardiovasc Ther, 2021, 2021:4971300. DOI: 10.1155/2021/4971300 .
37	SHIMAUCHI T, BOUCHERAT O, YOKOKAWA T, et al. PARP1-PKM2 axis mediates right ventricular failure associated with pulmonary arterial hypertension[J]. JACC Basic Transl Sci, 2022, 7(4):384-403. DOI: 10.1016/j.jacbts.2022.01.005 .
38	AKAZAWA Y, OKUMURA K, ISHII R, et al. Pulmonary artery banding is a relevant model to study the right ventricular remodeling and dysfunction that occurs in pulmonary arterial hypertension[J]. J Appl Physiol (1985), 2020, 129(2):238-246. DOI: 10.1152/japplphysiol.00148.2020 .
39	MENG L K, LIU X Y, ZHENG Z, et al. Original rat model of high kinetic unilateral pulmonary hypertension surgically induced by combined surgery[J]. J Thorac Cardiovasc Surg, 2013, 146(5):1220-1226.e1. DOI: 10.1016/j.jtcvs.2013.01.018 .
40	LACHANT D J, MEOLI D F, HAIGHT D, et al. Low dose monocrotaline causes a selective pulmonary vascular lesion in male and female pneumonectomized rats[J]. Exp Lung Res, 2018, 44(1):51-61. DOI: 10.1080/01902148.2017.1422157 .
41	KATZ M G, FARGNOLI A S, GUBARA S M, et al. The left pneumonectomy combined with monocrotaline or sugen as a model of pulmonary hypertension in rats[J]. J Vis Exp, 2019(145):10.3791/59050. DOI: 10.3791/59050 .
42	BISSERIER M, BOUCHERAT O, BONNET S, et al. Intra-airway gene delivery for pulmonary hypertension in rodent models[J]. Methods Mol Biol, 2022, 2573:263-278. DOI: 10.1007/978-1-0716-2707-5_20 .
43	YAN J, SHEN Y, WANG Y, et al. Increased expression of hypoxia-inducible factor-1α in proliferating neointimal lesions in a rat model of pulmonary arterial hypertension[J]. Am J Med Sci, 2013, 345(2):121-128. DOI: 10.1097/MAJ.0b013e31824cf5a2 .
44	DUAN Y, WANG T, WU S S, et al. The role of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway in the pulmonary vascular remodeling of pulmonary arterial hypertension in rats[J]. ScienceAsia, 2023, 49(1):56. DOI: 10.2306/scienceasia1513-1874.2023.130 .
45	MEDARAMETLA V, FESTIN S, SUGARRAGCHAA C, et al. PK10453, a nonselective platelet-derived growth factor receptor inhibitor, prevents the progression of pulmonary arterial hypertension[J]. Pulm Circ, 2014, 4(1):82-102. DOI: 10.1086/674881 .
46	SITAPARA R, SLEE D, SALTER-CID L, et al. Abstract 12947: In vivo efficacy of a novel, inhaled Pdgfra/b inhibitor, Gb002, in the rat monocrotaline and pneumonectomy model of pulmonary arterial hypertension[J]. Circulation, 2019, 140(): A12947. DOI:10.1161/circ.140.suppl_1.12947 .
47	BISSERIER M, KATZ M G, BUENO-BETI C, et al. Combination therapy with STAT3 inhibitor enhances SERCA2a-induced BMPR2 expression and inhibits pulmonary arterial hypertension[J]. Int J Mol Sci, 2021, 22(17):9105. DOI: 10.3390/ijms22179105 .
48	VAN DER FEEN D E, WEIJ M, SMIT-VAN OOSTEN A, et al. Shunt surgery, right heart catheterization, and vascular morphometry in a rat model for flow-induced pulmonary arterial hypertension[J]. J Vis Exp, 2017(120):55065. DOI: 10.3791/55065 .
49	VAN DER FEEN D E, KURAKULA K, TREMBLAY E, et al. Multicenter preclinical validation of BET inhibition for the treatment of pulmonary arterial hypertension[J]. Am J Respir Crit Care Med, 2019, 200(7):910-920. DOI: 10.1164/rccm.201812-2275OC .
50	VAN DER FEEN D E, BOSSERS G P L, HAGDORN Q A J, et al. Cellular senescence impairs the reversibility of pulmonary arterial hypertension[J]. Sci Transl Med, 2020, 12(554):eaaw4974. DOI: 10.1126/scitranslmed.aaw4974 .
51	ALAMRI A K, SHELBURNE N J, MAYEUX J D, et al. Pulmonary hypertension association's 2022 international conference scientific Sessions overview[J]. Pulm Circ, 2023, 13(1):e12182. DOI: 10.1002/pul2.12182 .
52	ZHOU J J, LI H, QIAN Y L, et al. Nestin represents a potential marker of pulmonary vascular remodeling in pulmonary arterial hypertension associated with congenital heart disease[J]. J Mol Cell Cardiol, 2020, 149:41-53. DOI: 10.1016/j.yjmcc.2020.09.005 .
53	ZHOU J J, LI H, LI L, et al. CYLD mediates human pulmonary artery smooth muscle cell dysfunction in congenital heart disease-associated pulmonary arterial hypertension[J]. J Cell Physiol, 2021, 236(9):6297-6311. DOI: 10.1002/jcp.30298 .
54	ZHOU J J, YANG J, LI L, et al. Transgelin exacerbates pulmonary artery smooth muscle cell dysfunction in shunt-related pulmonary arterial hypertension[J]. ESC Heart Fail, 2022, 9(5):3407-3417. DOI: 10.1002/ehf2.14080 .
55	ZHOU J J. Synemin promotes pulmonary artery smooth muscle cell phenotypic switch in shunt-induced pulmonary arterial hypertension[J]. ESC Heart Fail, 2022, 9(5):3221-3231. DOI: 10.1002/ehf2.14048 .
56	ZHOU J J, LI F R, YANG Y C. Protective effects of calcyclin-binding protein against pulmonary vascular remodeling in flow-associated pulmonary arterial hypertension[J]. Respir Res, 2022, 23(1):223. DOI: 10.1186/s12931-022-02137-z .
57	TARASEVICIENE-STEWART L, KASAHARA Y, ALGER L, et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension[J/OL]. FASEB J, 2001, 15(2): 427-438. DOI:10.1096/fj.00-0343com .
58	HURST L A, DUNMORE B J, LONG L, et al. TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling[J]. Nat Commun, 2017, 8:14079. DOI: 10.1038/ncomms14079 .
59	WU Z H, ZHU L, NIE X R, et al. USP15 promotes pulmonary vascular remodeling in pulmonary hypertension in a YAP1/TAZ-dependent manner[J]. Exp Mol Med, 2023, 55(1):183-195. DOI: 10.1038/s12276-022-00920-y .
60	SHEN H, ZHANG J, WANG C, et al. MDM2-mediated ubiquitination of angiotensin-converting enzyme 2 contributes to the development of pulmonary arterial hypertension[J]. Circulation, 2020, 142(12):1190-1204. DOI: 10.1161/CIRCULATIONAHA.120.048191 .
61	CLEMENTS R T, VANG A, FERNANDEZ-NICOLAS A, et al. Treatment of pulmonary hypertension with angiotensin II receptor blocker and neprilysin inhibitor sacubitril/valsartan[J]. Circ Heart Fail, 2019, 12(11):e005819. DOI: 10.1161/CIRCHEARTFAILURE.119.005819 .
62	BAO C L, HE Q, WANG H, et al. Artemisinin and its derivate alleviate pulmonary hypertension and vasoconstriction in rodent models[J]. Oxid Med Cell Longev, 2022, 2022:2782429. DOI: 10.1155/2022/2782429 .
63	JIA D L, BAI P Y, WAN N F, et al. Niacin attenuates pulmonary hypertension through H-PGDS in macrophages[J]. Circ Res, 2020, 127(10):1323-1336. DOI: 10.1161/CIRCRESAHA.120.316784 .
64	WANG L N, ZHANG X Y, CAO Y P, et al. Mice with a specific deficiency of Pfkfb3 in myeloid cells are protected from hypoxia-induced pulmonary hypertension[J]. Br J Pharmacol, 2021, 178(5):1055-1072. DOI: 10.1111/bph.15339 .
65	MACIAS D, MOORE S, CROSBY A, et al. Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for pulmonary arterial hypertension[J]. Eur Respir J, 2021, 57(3):1902061. DOI: 10.1183/13993003.02061-2019 .
66	DANEVA Z, CHEN Y L, TA H Q, et al. Endothelial IK and SK channel activation decreases pulmonary arterial pressure and vascular remodeling in pulmonary hypertension[J]. Pulm Circ, 2023, 13(1):e12186. DOI: 10.1002/pul2.12186 .
67	SUEN C M, CHAUDHARY K R, DENG Y P, et al. Fischer rats exhibit maladaptive structural and molecular right ventricular remodelling in severe pulmonary hypertension: a genetically prone model for right heart failure[J]. Cardiovasc Res, 2019, 115(4):788-799. DOI: 10.1093/cvr/cvy258 .
68	MORIMATSU Y, SAKASHITA N, KOMOHARA Y, et al. Development and characterization of an animal model of severe pulmonary arterial hypertension[J]. J Vasc Res, 2012, 49(1):33-42. DOI: 10.1159/000329594 .
69	INTERNATIONAL PPH CONSORTIUM, LANE K B, MACHADO R D, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension[J]. Nat Genet, 2000, 26(1):81-84. DOI: 10.1038/79226 .
70	DANNEWITZ PROSSEDA S, ALI M K, SPIEKERKOETTER E. Novel advances in modifying BMPR2 signaling in PAH[J]. Genes, 2020, 12(1):8. DOI: 10.3390/genes12010008 .
71	MACHADO R D, PAUCIULO M W, THOMSON J R, et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension[J]. Am J Hum Genet, 2001, 68(1):92-102. DOI: 10.1086/316947 .
72	BEPPU H, ICHINOSE F, KAWAI N, et al. BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia[J]. Am J Physiol Lung Cell Mol Physiol, 2004, 287(6):L1241-L1247. DOI: 10.1152/ajplung.00239.2004 .
73	LONG L, ORMISTON M L, YANG X D, et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension[J]. Nat Med, 2015, 21(7):777-785. DOI: 10.1038/nm.3877 .
74	HAUTEFORT A, MENDES-FERREIRA P, SABOURIN J, et al. Bmpr2 mutant rats develop pulmonary and cardiac characteristics of pulmonary arterial hypertension[J]. Circulation, 2019, 139(7):932-948. DOI: 10.1161/CIRCULATIONAHA.118.033744 .
75	TIAN W, JIANG X G, SUNG Y K, et al. Phenotypically silent bone morphogenetic protein receptor 2 mutations predispose rats to inflammation-induced pulmonary arterial hypertension by enhancing the risk for neointimal transformation[J]. Circulation, 2019, 140(17):1409-1425. DOI: 10.1161/CIRCULATIONAHA.119.040629 .
76	WEST J D, CHEN X P, PING L, et al. Adverse effects of BMPR2 suppression in macrophages in animal models of pulmonary hypertension[J]. Pulm Circ, 2019, 10(1):2045894019856483. DOI: 10.1177/2045894019856483 .
77	THEILMANN A L, HAWKE L G, HILTON L R, et al. Endothelial BMPR2 loss drives a proliferative response to BMP (bone morphogenetic protein) 9 via prolonged canonical signaling[J]. Arterioscler Thromb Vasc Biol, 2020, 40(11):2605-2618. DOI: 10.1161/ATVBAHA.119.313357 .
78	MORENO J, ESCOBEDO D, CALHOUN C, et al. Arterial wall stiffening in caveolin-1 deficiency-induced pulmonary artery hypertension in mice[J]. Exp Mech, 2021, 61(1):217-228. DOI: 10.1007/s11340-020-00666-6 .
79	LAMBERT M, CAPUANO V, BOET A, et al. Characterization of Kcnk3-mutated rat, a novel model of pulmonary hypertension[J]. Circ Res, 2019, 125(7):678-695. DOI: 10.1161/CIRCRESAHA.119.314793 .
80	WEST J D, AUSTIN E D, RIZZI E M, et al. KCNK3 mutation causes altered immune function in pulmonary arterial hypertension patients and mouse models[J]. Int J Mol Sci, 2021, 22(9):5014. DOI: 10.3390/ijms22095014 .
81	TU L, DESROCHES-CASTAN A, MALLET C, et al. Selective BMP-9 inhibition partially protects against experimental pulmonary hypertension[J]. Circ Res, 2019, 124(6):846-855. DOI: 10.1161/CIRCRESAHA.118.313356 .
82	BOUVARD C, TU L, ROSSI M, et al. Different cardiovascular and pulmonary phenotypes for single- and double-knock-out mice deficient in BMP9 and BMP10[J]. Cardiovasc Res, 2022, 118(7):1805-1820. DOI: 10.1093/cvr/cvab187 .
83	ZHANG Y N, ZERVOPOULOS S D, BOUKOURIS A E, et al. SNPs for genes encoding the mitochondrial proteins Sirtuin3 and uncoupling protein 2 are associated with disease severity, type 2 diabetes, and outcomes in patients with pulmonary arterial hypertension and this is recapitulated in a new mouse model lacking both genes[J]. J Am Heart Assoc, 2021, 10(23):e020451. DOI: 10.1161/JAHA.120.020451 .
84	DEMPSIE Y, NILSEN M, WHITE K, et al. Development of pulmonary arterial hypertension in mice over-expressing S100A4/Mts1 is specific to females[J]. Respir Res, 2011, 12(1):159. DOI: 10.1186/1465-9921-12-159 .
85	WEST J, RATHINASABAPATHY A, CHEN X P, et al. Overexpression of Msx1 in mouse lung leads to loss of pulmonary vessels following vascular hypoxic injury[J]. Cells, 2021, 10(9):2306. DOI: 10.3390/cells10092306 .
86	XUE C, SOWDEN M, BERK B C. Extracellular cyclophilin A, especially acetylated, causes pulmonary hypertension by stimulating endothelial apoptosis, redox stress, and inflammation[J]. Arterioscler Thromb Vasc Biol, 2017, 37(6):1138-1146. DOI: 10.1161/ATVBAHA.117.309212 .
87	XUE C, SENCHANTHISAI S, SOWDEN M, et al. Endothelial-to-mesenchymal transition and inflammation play key roles in cyclophilin A-induced pulmonary arterial hypertension[J]. Hypertension, 2020, 76(4):1113-1123. DOI: 10.1161/HYPERTENSIONAHA.119.14013 .
88	GALIÈ N, HUMBERT M, VACHIERY J L, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)[J]. Eur Heart J, 2016, 37(1):67-119. DOI: 10.1093/eurheartj/ehv317 .
89	KIM K H, KIM H K, CHAN S Y, et al. Hemodynamic and histopathologic benefits of early treatment with macitentan in a rat model of pulmonary arterial hypertension[J]. Korean Circ J, 2018, 48(9):839-853. DOI: 10.4070/kcj.2017.0394 .
90	LEE H, YEOM A, KIM K C, et al. Effect of ambrisentan therapy on the expression of endothelin receptor, endothelial nitric oxide synthase and NADPH oxidase 4 in monocrotaline-induced pulmonary arterial hypertension rat model[J]. Korean Circ J, 2019, 49(9):866-876. DOI: 10.4070/kcj.2019.0006 .
91	NOVELLI D, FUMAGALLI F, STASZEWSKY L, et al. Monocrotaline-induced pulmonary arterial hypertension: time-course of injury and comparative evaluation of macitentan and Y-27632, a Rho kinase inhibitor[J]. Eur J Pharmacol, 2019, 865:172777. DOI: 10.1016/j.ejphar. 2019. 172777 .
92	CHAUMAIS M C, DJESSAS M R A, THUILLET R, et al. Additive protective effects of sacubitril/valsartan and bosentan on vascular remodelling in experimental pulmonary hypertension[J]. Cardiovasc Res, 2021, 117(5):1391-1401. DOI: 10.1093/cvr/cvaa200 .
93	ZHANG Z Y, LIU C L, BAI Y Y, et al. Pipersentan: a de novo synthetic endothelin receptor antagonist that inhibits monocrotaline- and hypoxia-induced pulmonary hypertension[J]. Front Pharmacol, 2022, 13:920222. DOI: 10.3389/fphar. 2022.920222 .
94	VELASOVA E, LELKOVA K, VETESKOVA J, et al. Riociguat normalizes altered lung expression of serotonin-related genes and renal damage markers in experimental pulmonary hypertension[J]. Eur Heart J, 2022, 43():ehac544.1922. DOI: 10.1093/eurheartj/ehac544.1922 .
95	XU X, LI H L, WEI Q X, et al. Novel targets in a high-altitude pulmonary hypertension rat model based on RNA-seq and proteomics[J]. Front Med (Lausanne), 2021, 8:742436. DOI: 10.3389/fmed.2021.742436 .
96	SILVA M M C D, ALENCAR A K N, SILVA J S D, et al. Therapeutic benefit of the association of lodenafil with mesenchymal stem cells on hypoxia-induced pulmonary hypertension in rats[J]. Cells, 2020, 9(9):2120. DOI: 10.3390/cells9092120 .
97	CHAUDHARY K R, DENG Y P, SUEN C M, et al. Efficacy of treprostinil in the SU5416-hypoxia model of severe pulmonary arterial hypertension: haemodynamic benefits are not associated with improvements in arterial remodelling[J]. Br J Pharmacol, 2018, 175(20):3976-3989. DOI: 10.1111/bph.14472 .
98	VANDERPOOL R R, GORELOVA A, MA Y R, et al. Reversal of right ventricular hypertrophy and dysfunction by prostacyclin in a rat model of severe pulmonary arterial hypertension[J]. Int J Mol Sci, 2022, 23(10):5426. DOI: 10.3390/ijms23105426 .
99	MORRISON K, HAAG F, ERNST R, et al. Selective prostacyclin receptor agonist selexipag, in contrast to prostacyclin analogs, does not evoke paradoxical vasoconstriction of the rat femoral artery[J]. J Pharmacol Exp Ther, 2018, 365(3):727-733. DOI: 10.1124/jpet.117.246058 .
100	HONDA Y, KOSUGI K, FUCHIKAMI C, et al. The selective PGI2 receptor agonist selexipag ameliorates Sugen 5416/hypoxia-induced pulmonary arterial hypertension in rats[J]. PLoS One, 2020, 15(10):e0240692. DOI: 10.1371/journal.pone.0240692 .
101	CORBOZ M R, PLAUNT A J, MALININ V S, et al. Assessment of inhaled treprostinil palmitil, inhaled and intravenous treprostinil, and oral selexipag in a sugen/hypoxia rat model of pulmonary arterial hypertension[J]. J Pharmacol Exp Ther, 2022, 383(1):103-116. DOI: 10.1124/jpet.122.001174 .
102	RAI N, SHIHAN M, SEEGER W, et al. Genetic delivery and gene therapy in pulmonary hypertension[J]. Int J Mol Sci, 2021, 22(3):1179. DOI: 10.3390/ijms22031179 .
103	BISSERIER M, PRADHAN N, HADRI L. Current and emerging therapeutic approaches to pulmonary hypertension[J]. Rev Cardiovasc Med, 2020, 21(2):163-179. DOI: 10.31083/j.rcm.2020.02.597 .

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