Molecular Mechanisms of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

Jane A Leopold, Bradley A Maron, Jane A Leopold, Bradley A Maron

Abstract

Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype.

Keywords: DNA damage; endothelial-to-mesenchymal transition; metabolism; microRNA; mitochondria; pulmonary arterial hypertension.

Figures

Figure 1
Figure 1
Metabolism in PAH. Metabolism in PAH is perturbed akin to what is observed in cancer. Glycolysis occurs when glucose is taken up by the glucose transporters-1 (GLUT-1) and -4 (GLUT-4), gets phosphorylated by hexokinase (HK), and goes through a series of reactions to produce pyruvate. Pyruvate is the substrate for pyruvate dehydrogenase (PDH) in the mitochondria to support glucose oxidation. Free fatty acids (FFA) are taken up by fatty acid transport protein-1 (FATP-1) and -6 (FATP-6) and transformed to acyl carnitines that are shuttled across the mitochondrial membrane by carnitine palmitoyltransferase-1 (CPT1) and transformed to acyl CoA by carnitine palmitoyltransferase-2 (CPT2). Acyl CoA is converted to acetyl CoA during β-oxidation. In PAH, there is increased aerobic glycolysis due to normoxic upregulation of HIF-1α, which upregulates pyruvate dehydrogenase kinase (PDK) to inhibit pyruvate dehydrogenase, and epigenetic regulation of the superoxide dismutase 2 (SOD2) gene. PFK, phosphofructokinase; PK, pyruvate kinase; LDH, lactate dehydrogenase; ROS, reactive oxygen species; ETC, electron transport chain.
Figure 2
Figure 2
Endothelial-to-mesenchymal transition. Endothelial-to-mesenchymal transition (EndoMT) occurs when the endothelium is exposed to environmental stressors that increase levels of transforming growth factor-β (TGFβ), tumor necrosis factor-α (TNF-α), or interleukin-1β (IL-1β). These factors activate a select population of endothelial cells, which lose their endothelial markers (i.e., CD31, vascular endothelial cadherin (VE-cadherin), and von Willibrand factor (vWF)) and lose tight gap junctions between cells (double lines). These endothelial cells then express α-smooth muscle actin (α-SMA) and vimentin. Cells may also acquire a mesenchymal phenotype and express fibronectin, N-cadherin, and the EndoMT-related transcription factor Twist.

References

    1. Hoeper M.M., Bogaard H.J., Condliffe R., Frantz R., Khanna D., Kurzyna M., Langleben D., Manes A., Satoh T., Torres F., et al. Definitions and diagnosis of pulmonary hypertension. J. Am. Coll. Cardiol. 2013;62:D42–D50. doi: 10.1016/j.jacc.2013.10.032.
    1. Ling Y., Johnson M.K., Kiely D.G., Condliffe R., Elliot C.A., Gibbs J.S., Howard L.S., Pepke-Zaba J., Sheares K.K., Corris P.A., et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: Results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am. J. Respir. Crit. Care Med. 2012;186:790–796. doi: 10.1164/rccm.201203-0383OC.
    1. McGoon M.D., Benza R.L., Escribano-Subias P., Jiang X., Miller D.P., Peacock A.J., Pepke-Zaba J., Pulido T., Rich S., Rosenkranz S., et al. Pulmonary arterial hypertension: Epidemiology and registries. J. Am. Coll. Cardiol. 2013;62:D51–D59. doi: 10.1016/j.jacc.2013.10.023.
    1. Tuder R.M., Archer S.L., Dorfmuller P., Erzurum S.C., Guignabert C., Michelakis E., Rabinovitch M., Schermuly R., Stenmark K.R., Morrell N.W. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J. Am. Coll. Cardiol. 2013;62:D4–D12. doi: 10.1016/j.jacc.2013.10.025.
    1. International P.P.H.C., Lane K.B., Machado R.D., Pauciulo M.W., Thomson J.R., Phillips J.A., 3rd, Loyd J.E., Nichols W.C., Trembath R.C. Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. Nat. Genet. 2000;26:81–84.
    1. Deng Z., Haghighi F., Helleby L., Vanterpool K., Horn E.M., Barst R.J., Hodge S.E., Morse J.H., Knowles J.A. Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33. Am. J. Respir. Crit. Care Med. 2000;161:1055–109. doi: 10.1164/ajrccm.161.3.9906051.
    1. Thomson J., Machado R., Pauciulo M., Morgan N., Yacoub M., Corris P., McNeil K., Loyd J., Nichols W., Trembath R. Familial and sporadic primary pulmonary hypertension is caused by BMPR2 gene mutations resulting in haploinsufficiency of the bone morphogenetic protein tuype II receptor. J. Heart Lung Transplant. 2001;20:149. doi: 10.1016/S1053-2498(01)00259-5.
    1. Machado R.D., Southgate L., Eichstaedt C.A., Aldred M.A., Austin E.D., Best D.H., Chung W.K., Benjamin N., Elliott C.G., Eyries M., et al. Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Hum. Mutat. 2015;36:1113–1127. doi: 10.1002/humu.22904.
    1. Austin E.D., Ma L., LeDuc C., Rosenzweig E.B., Borczuk A., Phillips J.A., III, Palomero T., Sumazin P., Kim H.R., Talati M.H., et al. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ. Cardiovasc. Genet. 2012;5:336–343. doi: 10.1161/CIRCGENETICS.111.961888.
    1. Ma L., Roman-Campos D., Austin E.D., Eyries M., Sampson K.S., Soubrier F., Germain M., Tregouet D.A., Borczuk A., Rosenzweig E.B., et al. A novel channelopathy in pulmonary arterial hypertension. N. Engl. J. Med. 2013;369:351–361. doi: 10.1056/NEJMoa1211097.
    1. Eyries M., Montani D., Girerd B., Perret C., Leroy A., Lonjou C., Chelghoum N., Coulet F., Bonnet D., Dorfmuller P., et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat. Genet. 2014;46:65–69. doi: 10.1038/ng.2844.
    1. Germain M., Eyries M., Montani D., Poirier O., Girerd B., Dorfmuller P., Coulet F., Nadaud S., Maugenre S., Guignabert C., et al. Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat. Genet. 2013;45:518–521. doi: 10.1038/ng.2581.
    1. Wang G., Knight L., Ji R., Lawrence P., Kanaan U., Li L., Das A., Cui B., Zou W., Penny D.J., et al. Early onset severe pulmonary arterial hypertension with “two-hit” digenic mutations in both BMPR2 and KCNA5 genes. Int. J. Cardiol. 2014;177:e167–e169. doi: 10.1016/j.ijcard.2014.08.124.
    1. Lee S.D., Shroyer K.R., Markham N.E., Cool C.D., Voelkel N.F., Tuder R.M. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J. Clin. Investig. 1998;101:927–934. doi: 10.1172/JCI1910.
    1. Tuder R.M., Lee S.D., Cool C.C. Histopathology of pulmonary hypertension. Chest. 1998;114:1S–6S. doi: 10.1378/chest.114.1_Supplement.1S-a.
    1. Yeager M.E., Halley G.R., Golpon H.A., Voelkel N.F., Tuder R.M. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ. Res. 2001;88:E2–E11. doi: 10.1161/01.RES.88.1.e2.
    1. Aldred M.A., Comhair S.A., Varella-Garcia M., Asosingh K., Xu W., Noon G.P., Thistlethwaite P.A., Tuder R.M., Erzurum S.C., Geraci M.W., et al. Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2010;182:1153–1160. doi: 10.1164/rccm.201003-0491OC.
    1. Meloche J., Pflieger A., Vaillancourt M., Paulin R., Potus F., Zervopoulos S., Graydon C., Courboulin A., Breuils-Bonnet S., Tremblay E., et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation. 2014;129:786–797. doi: 10.1161/CIRCULATIONAHA.113.006167.
    1. De Jesus Perez V.A., Yuan K., Lyuksyutova M.A., Dewey F., Orcholski M.E., Shuffle E.M., Mathur M., Yancy L., Jr., Rojas V., Li C.G., et al. Whole-exome sequencing reveals TopBP1 as a novel gene in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2014;189:1260–1272. doi: 10.1164/rccm.201310-1749OC.
    1. Federici C., Drake K.M., Rigelsky C.M., McNelly L.N., Meade S.L., Comhair S.A., Erzurum S.C., Aldred M.A. Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension. Am. J. Respir. Crit. Care Med. 2015;192:219–228. doi: 10.1164/rccm.201411-2128OC.
    1. Li M., Vattulainen S., Aho J., Orcholski M., Rojas V., Yuan K., Helenius M., Taimen P., Myllykangas S., de Jesus Perez V., et al. Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension. Am. J. Respir. Cell Mol. Biol. 2014;50:1118–1128. doi: 10.1165/rcmb.2013-0349OC.
    1. Ambros V. microRNAs: Tiny regulators with great potential. Cell. 2001;107:823–826. doi: 10.1016/S0092-8674(01)00616-X.
    1. Courboulin A., Paulin R., Giguere N.J., Saksouk N., Perreault T., Meloche J., Paquet E.R., Biardel S., Provencher S., Cote J., et al. Role for miR-204 in human pulmonary arterial hypertension. J. Exp. Med. 2011;208:535–548. doi: 10.1084/jem.20101812.
    1. Rhodes C.J., Wharton J., Boon R.A., Roexe T., Tsang H., Wojciak-Stothard B., Chakrabarti A., Howard L.S., Gibbs J.S., Lawrie A., et al. Reduced microRNA-150 is associated with poor survival in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2013;187:294–302. doi: 10.1164/rccm.201205-0839OC.
    1. Bockmeyer C.L., Maegel L., Janciauskiene S., Rische J., Lehmann U., Maus U.A., Nickel N., Haverich A., Hoeper M.M., Golpon H.A., et al. Plexiform vasculopathy of severe pulmonary arterial hypertension and microRNA expression. J. Heart Lung Transplant. 2012;31:764–772. doi: 10.1016/j.healun.2012.03.010.
    1. Zhou G., Chen T., Raj J.U. MicroRNAs in pulmonary arterial hypertension. Am. J. Respir. Cell Mol. Biol. 2015;52:139–151. doi: 10.1165/rcmb.2014-0166TR.
    1. Caruso P., MacLean M.R., Khanin R., McClure J., Soon E., Southgate M., MacDonald R.A., Greig J.A., Robertson K.E., Masson R., et al. Dynamic Changes in Lung MicroRNA Profiles During the Development of Pulmonary Hypertension due to Chronic Hypoxia and Monocrotaline. Arterioscler. Thromb. Vasc. Biol. 2010;30:716–723. doi: 10.1161/ATVBAHA.109.202028.
    1. White K., Lu Y., Annis S., Hale A.E., Chau B.N., Dahlman J.E., Hemann C., Opotowsky A.R., Vargas S.O., Rosas I., et al. Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Mol. Med. 2015;7:695–713. doi: 10.15252/emmm.201404511.
    1. Potus F., Ruffenach G., Dahou A., Thebault C., Breuils-Bonnet S., Tremblay È., Nadeau V., Paradis R., Graydon C., Wong R., et al. Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension. Circulation. 2015;132:932–943. doi: 10.1161/CIRCULATIONAHA.115.016382.
    1. Stevens H.C., Deng L., Grant J.S., Pinel K., Thomas M., Morrell N.W., MacLean M.R., Baker A.H., Denby L. Regulation and function of miR-214 in pulmonary arterial hypertension. Pulm. Circ. 2016;6:109–117. doi: 10.1086/685079.
    1. Brock M., Trenkmann M., Gay R.E., Michel B.A., Gay S., Fischler M., Ulrich S., Speich R., Huber L.C. Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ. Res. 2009;104:1184–1191. doi: 10.1161/CIRCRESAHA.109.197491.
    1. Pullamsetti S.S., Doebele C., Fischer A., Savai R., Kojonazarov B., Dahal B.K., Ghofrani H.A., Weissmann N., Grimminger F., Bonauer A., et al. Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am. J. Respir. Crit. Care Med. 2012;185:409–419. doi: 10.1164/rccm.201106-1093OC.
    1. Cordes K.R., Sheehy N.T., White M.P., Berry E.C., Morton S.U., Muth A.N., Lee T.H., Miano J.M., Ivey K.N., Srivastava D. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009;460:705–710. doi: 10.1038/nature08195.
    1. Boettger T., Beetz N., Kostin S., Schneider J., Kruger M., Hein L., Braun T. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the miR143/145 gene cluster. J. Clin. Investig. 2009;119:2634–2647. doi: 10.1172/JCI38864.
    1. Courboulin A., Tremblay V.L., Barrier M., Meloche J., Jacob M.H., Chapolard M., Bisserier M., Paulin R., Lambert C., Provencher S., et al. Kruppel-like factor 5 contributes to pulmonary artery smooth muscle proliferation and resistance to apoptosis in human pulmonary arterial hypertension. Respir. Res. 2011;12:128. doi: 10.1186/1465-9921-12-128.
    1. Caruso P., Dempsie Y., Stevens H.C., McDonald R.A., Long L., Lu R., White K., Mair K.M., McClure J.D., Southwood M., et al. A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circ. Res. 2012;111:290–300. doi: 10.1161/CIRCRESAHA.112.267591.
    1. Lee C., Mitsialis S.A., Aslam M., Vitali S.H., Vergadi E., Konstantinou G., Sdrimas K., Fernandez-Gonzalez A., Kourembanas S. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. 2012;126:2601–2611. doi: 10.1161/CIRCULATIONAHA.112.114173.
    1. Parikh V.N., Jin R.C., Rabello S., Gulbahce N., White K., Hale A., Cottrill K.A., Shaik R.S., Waxman A.B., Zhang Y.Y., et al. MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach. Circulation. 2012;125:1520–1532. doi: 10.1161/CIRCULATIONAHA.111.060269.
    1. Bertero T., Cottrill K., Krauszman A., Lu Y., Annis S., Hale A., Bhat B., Waxman A.B., Chau B.N., Kuebler W.M., et al. The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension. J. Biol. Chem. 2015;290:2069–2085. doi: 10.1074/jbc.M114.617845.
    1. Bertero T., Lu Y., Annis S., Hale A., Bhat B., Saggar R., Saggar R., Wallace W.D., Ross D.J., Vargas S.O., et al. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J. Clin. Investig. 2014;124:3514–3528. doi: 10.1172/JCI74773.
    1. Paulin R., Michelakis E.D. The metabolic theory of pulmonary arterial hypertension. Circ. Res. 2014;115:148–164. doi: 10.1161/CIRCRESAHA.115.301130.
    1. Kennedy E.P., Lehninger A.L. Oxidation of fatty acids and tricarboxylic acid cycle intermediates by isolated rat liver mitochondria. J. Biol. Chem. 1949;179:957–972.
    1. Randle P.J., Garland P.B., Hales C.N., Newsholme E.A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1:785–789. doi: 10.1016/S0140-6736(63)91500-9.
    1. Warburg O., Wind F., Negelein E. The metabolism of tumors in the body. J. Gen. Physiol. 1927;8:519–530. doi: 10.1085/jgp.8.6.519.
    1. Archer S.L. Mitochondrial dynamics—Mitochondrial fission and fusion in human diseases. N. Engl. J. Med. 2013;369:2236–2251.
    1. Yu A.Y., Shimoda L.A., Iyer N.V., Huso D.L., Sun X., McWilliams R., Beaty T., Sham J.S., Wiener C.M., Sylvester J.T., et al. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. J. Clin. Investig. 1999;103:691–696. doi: 10.1172/JCI5912.
    1. Piao L., Sidhu V.K., Fang Y.H., Ryan J.J., Parikh K.S., Hong Z., Toth P.T., Morrow E., Kutty S., Lopaschuk G.D., 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. Mol. Med. 2013;3:333–346. doi: 10.1007/s00109-012-0982-0.
    1. Xu W., Koeck T., Lara A.R., Neumann D., DiFilippo F.P., Koo M., Janocha A.J., Masri F.A., Arroliga A.C., Jennings C., et al. Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc. Natl. Acad. Sci. USA. 2007;104:1342–1347. doi: 10.1073/pnas.0605080104.
    1. Marsboom G., Toth P.T., Ryan J.J., Hong Z., Wu X., Fang Y.H., Thenappan T., Piao L., Zhang H.J., Pogoriler J., et al. Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circ. Res. 2012;110:1484–1497. doi: 10.1161/CIRCRESAHA.111.263848.
    1. Archer S.L., Marsboom G., Kim G.H., Zhang H.J., Toth P.T., Svensson E.C., Dyck J.R., Gomberg-Maitland M., Thébaud B., Husain A.N., et al. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: A basis for excessive cell proliferation and a new therapeutic target. Circulation. 2010;121:2661–2671. doi: 10.1161/CIRCULATIONAHA.109.916098.
    1. Guignabert C., Tu L., Izikki M., Dewachter L., Zadigue P., Humbert M., Adnot S., Fadel E., Eddahibi S. Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22α-targeted overexpression of the serotonin transporter. FASEB J. 2009;23:4135–4147. doi: 10.1096/fj.09-131664.
    1. Bonnet S., Michelakis E.D., Porter C.J., Andrade-Navarro M.A., Thebaud B., Bonnet S., Haromy A., Harry G., Moudgil R., McMurtry M.S., et al. An abnormal mitochondrial-hypoxia inducible factor-1α-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: Similarities to human pulmonary arterial hypertension. Circulation. 2006;113:2630–2641. doi: 10.1161/CIRCULATIONAHA.105.609008.
    1. McMurtry M.S., Bonnet S., Wu X., Dyck J.R., Haromy A., Hashimoto K., Michelakis E.D. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ. Res. 2004;95:830–840. doi: 10.1161/01.RES.0000145360.16770.9f.
    1. Archer S.L., Gomberg-Maitland M., Maitland M.L., Rich S., Garcia J.G., Weir E.K. Mitochondrial metabolism, redox signaling, and fusion: A mitochondria-ROS-HIF-1α-Kv1.5O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am. J. Physiol. Heart Circ. Physiol. 2008;294:H570–H578. doi: 10.1152/ajpheart.01324.2007.
    1. Zhao L., Oliver E., Maratou K., Atanur S.S., Dubois O.D., Cotroneo E., Chen C.N., Wang L., Arce C., Chabosseau P.L., et al. The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia. Nature. 2015;524:356–360. doi: 10.1038/nature14620.
    1. Cotroneo E., Ashek A., Wang L., Wharton J., Dubois O., Bozorgi S., Busbridge M., Alavian K.N., Wilkins M.R., Zhao L. Iron homeostasis and pulmonary hypertension: Iron deficiency leads to pulmonary vascular remodeling in the rat. Circ. Res. 2015;116:1680–1690. doi: 10.1161/CIRCRESAHA.116.305265.
    1. Ruiter G., Manders E., Happe C.M., Schalij I., Groepenhoff H., Howard L.S., Wilkins M.R., Bogaard H.J., Westerhof N., van der Laarse W.J., et al. Intravenous iron therapy in patients with idiopathic pulmonary arterial hypertension and iron deficiency. Pulm. Circ. 2015;5:466–472. doi: 10.1086/682217.
    1. Bonnet S., Rochefort G., Sutendra G., Archer S.L., Haromy A., Webster L., Hashimoto K., Bonnet S.N., Michelakis E.D. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc. Natl. Acad. Sci. USA. 2007;104:11418–11423. doi: 10.1073/pnas.0610467104.
    1. Kuga T., Kobayashi S., Hirakawa Y., Kanaide H., Takeshita A. Cell cycle—Dependent expression of L- and T-type Ca2+ currents in rat aortic smooth muscle cells in primary culture. Circ. Res. 1996;79:14–19. doi: 10.1161/01.RES.79.1.14.
    1. Peng G., Li S., Hong W., Hu J., Jiang Y., Hu G., Zou Y., Zhou Y., Xu J., Ran P. Chronic Hypoxia Increases Intracellular Ca2+ Concentration via Enhanced Ca2+ Entry Through Receptor-Operated Ca2+ Channels in Pulmonary Venous Smooth Muscle Cells. Circ. J. 2015;79:2058–2068. doi: 10.1253/circj.CJ-15-0067.
    1. Fernandez R.A., Wan J., Song S., Smith K.A., Gu Y., Tauseef M., Tang H., Makino A., Mehta D., Yuan J.X. Upregulated expression of STIM2, TRPC6, and Orai2 contributes to the transition of pulmonary arterial smooth muscle cells from a contractile to proliferative phenotype. Am. J. Physiol. Cell Physiol. 2015;308:C581–C593. doi: 10.1152/ajpcell.00202.2014.
    1. Gilbert G., Ducret T., Marthan R., Savineau J.P., Quignard J.F. Stretch-induced Ca2+ signalling in vascular smooth muscle cells depends on Ca2+ store segregation. Cardiovasc. Res. 2014;103:313–323. doi: 10.1093/cvr/cvu069.
    1. Hadri L., Kratlian R.G., Benard L., Maron B.A., Dorfmuller P., Ladage D., Guignabert C., Ishikawa K., Aguero J., Ibanez B., et al. Therapeutic efficacy of AAV1.SERCA2a in monocrotaline-induced pulmonary arterial hypertension. Circulation. 2013;128:512–523. doi: 10.1161/CIRCULATIONAHA.113.001585.
    1. Aguero J., Ishikawa K., Hadri L., Santos-Gallego C., Fish K., Kohlbrenner E., Hammoudi N., Kho C., Lee A., Ibanez B., et al. Intratracheal gene delivery of SERCA2a amerliorates chronic post-capillary pulmonary hypertension: A large animal model. J. Am. Coll. Cardiol. 2016;67:2032–2046. doi: 10.1016/j.jacc.2016.02.049.
    1. Aguero J., Ishikawa K., Hadri L., Santos-Gallego C., Fish K., Hammoudi N., Chaanine A., Torquato S., Naim C., Ibanez B., et al. Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model. Am. J. Physiol. Heart Circ. Physiol. 2014;307:H1204–H1215. doi: 10.1152/ajpheart.00246.2014.
    1. Frid M.G., Kale V.A., Stenmark K.R. Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circ. Res. 2002;90:1189–1196. doi: 10.1161/01.RES.0000021432.70309.28.
    1. Krenning G., Barauna V.G., Krieger J.E., Harmsen M.C., Moonen J.R. Endothelial Plasticity: Shifting Phenotypes through Force Feedback. Stem Cells Int. 2016;2016:9762959. doi: 10.1155/2016/9762959.
    1. Ranchoux B., Antigny F., Rucker-Martin C., Hautefort A., Pechoux C., Bogaard H.J., Dorfmuller P., Remy S., Lecerf F., Plante S., et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation. 2015;131:1006–1018. doi: 10.1161/CIRCULATIONAHA.114.008750.
    1. Good R.B., Gilbane A.J., Trinder S.L., Denton C.P., Coghlan G., Abraham D.J., Holmes A.M. Endothelial to Mesenchymal Transition Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension. Am. J. Pathol. 2015;185:1850–1858. doi: 10.1016/j.ajpath.2015.03.019.
    1. Qiao L., Nishimura T., Shi L., Sessions D., Thrasher A., Trudell J.R., Berry G.J., Pearl R.G., Kao P.N. Endothelial fate mapping in mice with pulmonary hypertension. Circulation. 2014;129:692–703. doi: 10.1161/CIRCULATIONAHA.113.003734.
    1. Sheikh A.Q., Lighthouse J.K., Greif D.M. Recapitulation of developing artery muscularization in pulmonary hypertension. Cell Rep. 2014;6:809–817. doi: 10.1016/j.celrep.2014.01.042.
    1. Sheikh A.Q., Misra A., Rosas I.O., Adams R.H., Greif D.M. Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension. Sci. Transl. Med. 2015;7:308ra159. doi: 10.1126/scitranslmed.aaa9712.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera