Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2

American Journal of Physiology - Lung Cellular and Molecular Physiology

Volumn 313, Issue 3, 2017, Pages L628-L647

  Dieffenbach, Paul B ^a   Haeger, Christina Mallarino ^a   Coronata, Anna Maria F ^a   Choi, Kyoung Moo ^b   Varelas, Xaralabos ^c   Tschumperlin, Daniel J ^b   Fredenburgh, Laura E ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b MAYO GRADUATE SCHOOL   (United States)

^c BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

COX 2; Matrix stiffness; Prostaglandins; Pulmonary hypertension; YAP TAZ

Indexed keywords

COLLAGEN; CYCLOOXYGENASE 2; ELASTIN; LENTIVIRUS VECTOR; MESSENGER RNA; PROSTAGLANDIN; SMALL INTERFERING RNA; TRANSCRIPTION FACTOR YAP1; APOPTOSIS REGULATORY PROTEIN; PHOSPHOPROTEIN; SIGNAL PEPTIDE; SIGNAL TRANSDUCING ADAPTOR PROTEIN; WWTR1 PROTEIN, HUMAN; WWTR1 PROTEIN, RAT; YAP PROTEIN, RAT; YAP1 (YES-ASSOCIATED) PROTEIN, HUMAN;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTERIAL STIFFNESS; ARTICLE; CELL COUNT; COMPARATIVE STUDY; CONTROLLED STUDY; EXPERIMENTAL PULMONARY HYPERTENSION; FEEDBACK SYSTEM; GENE EXPRESSION; GENETIC TRANSFECTION; IMMUNOFLUORESCENCE; LIMIT OF QUANTITATION; MALE; MECHANOTRANSDUCTION; MORTALITY; NONHUMAN; PHENOTYPE; POSITIVE FEEDBACK; PRIORITY JOURNAL; PROTEIN CROSS LINKING; PROTEIN EXPRESSION; PULMONARY ARTERY; QUANTITATIVE ANALYSIS; RAT; RNA INTERFERENCE; SIGNAL TRANSDUCTION; SMOOTH MUSCLE CELL; TRANSIENT TRANSFECTION; WESTERN BLOTTING; AIRWAY REMODELING; ANIMAL; CELL MOTION; CELL PROLIFERATION; CYTOLOGY; DEMOGRAPHY; EXTRACELLULAR MATRIX; FEMALE; GENE SILENCING; HUMAN; METABOLISM; MIDDLE AGED; PHYSIOLOGY; PULMONARY HYPERTENSION; SPRAGUE DAWLEY RAT;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ADULT; AIRWAY REMODELING; ANIMALS; APOPTOSIS REGULATORY PROTEINS; CELL MOVEMENT; CELL PROLIFERATION; CYCLOOXYGENASE 2; DEMOGRAPHY; EXTRACELLULAR MATRIX; FEMALE; GENE KNOCKDOWN TECHNIQUES; HUMANS; HYPERTENSION, PULMONARY; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MALE; MIDDLE AGED; MYOCYTES, SMOOTH MUSCLE; PHENOTYPE; PHOSPHOPROTEINS; PULMONARY ARTERY; RATS, SPRAGUE-DAWLEY; SIGNAL TRANSDUCTION; VASCULAR STIFFNESS;

EID: 85028730101     PISSN: 10400605     EISSN: 15221504     Source Type: Journal    
DOI: 10.1152/ajplung.00173.2017     Document Type: Article

References (89)

1. Al-Naamani N, Preston IR, Paulus JK, Hill NS, Roberts KE. Pulmonary arterial capacitance is an important predictor of mortality in heart failure with a preserved ejection fraction. JACC Heart Fail 3: 467-474, 2015. doi:10.1016/j.jchf.2015.01.013.
2. Al-Naamani N, Sagliani KD, Dolnikowski GG, Warburton RR, Toksoz D, Kayyali U, Hill NS, Fanburg BL, Roberts KE, Preston IR. Plasma 12- and 15-hydroxyeicosanoids are predictors of survival in pulmonary arterial hypertension. Pulm Circ 6: 224-233, 2016. doi:10.1086/686311.
3. Aragona M, Panciera T, Manfrin A, Giulitti S, Michielin F, Elvassore N, Dupont S, Piccolo S. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154: 1047-1059, 2013. doi:10.1016/j.cell.2013.07.042.
4. Aytekin M, Comhair SA, de la Motte C, Bandyopadhyay SK, Farver CF, Hascall VC, Erzurum SC, Dweik RA. High levels of hyaluronan in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 295: L789-L799, 2008. doi:10.1152/ajplung.90306.2008.
5. Bertero T, Cottrill KA, Lu Y, Haeger CM, Dieffenbach P, Annis S, Hale A, Bhat B, Kaimal V, Zhang YY, Graham BB, Kumar R, Saggar R, Saggar R, Wallace WD, Ross DJ, Black SM, Fratz S, Fineman JR, Vargas SO, Haley KJ, Waxman AB, Chau BN, Fredenburgh LE, Chan SY. Matrix remodeling promotes pulmonary hypertension through feedback mechanoactivation of the YAP/TAZ-miR-130/301 circuit. Cell Reports 13: 1016-1032, 2015. doi:10.1016/j.celrep.2015.09.049.
6. Bertero T, Oldham WM, Cottrill KA, Pisano S, Vanderpool RR, Yu Q, Zhao J, Tai Y, Tang Y, Zhang YY, Rehman S, Sugahara M, Qi Z, Gorcsan J III, Vargas SO, Saggar R, Saggar R, Wallace WD, Ross DJ, Haley KJ, Waxman AB, Parikh VN, De Marco T, Hsue PY, Morris A, Simon MA, Norris KA, Gaggioli C, Loscalzo J, Fessel J, Chan SY. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest 126: 3313-3335, 2016. doi:10.1172/JCI86387.
7. Beyer TA, Weiss A, Khomchuk Y, Huang K, Ogunjimi AA, Varelas X, Wrana JL. Switch enhancers interpret TGF-β and Hippo signaling to control cell fate in human embryonic stem cells. Cell Reports 5: 1611-1624, 2013. doi:10.1016/j.celrep.2013.11.021.
8. Brittain EL, Pugh ME, Wheeler LA, Robbins IM, Loyd JE, Newman JH, Austin ED, Hemnes AR. Prostanoids but not oral therapies improve right ventricular function in pulmonary arterial hypertension. JACC Heart Fail 1: 300-307, 2013. doi:10.1016/j.jchf.2013.05.004.
9. Butler JP, Tolić-Nørrelykke IM, Fabry B, Fredberg JJ. Traction fields, moments, and strain energy that cells exert on their surroundings. Am J Physiol Cell Physiol 282: C595-C605, 2002. doi:10.1152/ajpcell.00270.2001.
10. Castelain V, Hervé P, Lecarpentier Y, Duroux P, Simonneau G, Chemla D. Pulmonary artery pulse pressure and wave reflection in chronic pulmonary thromboembolism and primary pulmonary hypertension. J Am Coll Cardiol 37: 1085-1092, 2001. doi:10.1016/S0735-1097(00)01212-2.
11. Chariyalertsak S, Sirikulchayanonta V, Mayer D, Kopp-Schneider A, Fürstenberger G, Marks F, Müller-Decker K. Aberrant cyclooxygenase isozyme expression in human intrahepatic cholangiocarcinoma. Gut 48:80-86, 2001. doi:10.1136/gut.48.1.80.
12. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, Loyd JE. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 327: 70-75, 1992. doi:10.1056/NEJM199207093270202.
13. Comhair SA, Xu W, Mavrakis L, Aldred MA, Asosingh K, Erzurum SC. Human primary lung endothelial cells in culture. Am J Respir Cell Mol Biol 46: 723-730, 2012. doi:10.1165/rcmb.2011-0416TE.
14. Delcroix M, Spaas K, Quarck R. Long-term outcome in pulmonary arterial hypertension: a plea for earlier parenteral prostacyclin therapy. Eur Respir Rev 18: 253-259, 2009. doi:10.1183/09059180.00003109.
15. Douwes JM, Roofthooft MT, Bartelds B, Talsma MD, Hillege HL, Berger RM. Pulsatile haemodynamic parameters are predictors of survival in paediatric pulmonary arterial hypertension. Int J Cardiol 168:1370-1377, 2013. doi:10.1016/j.ijcard.2012.12.080.
16. Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S. Role of YAP/TAZ in mechanotransduction. Nature 474: 179-183, 2011. doi:10.1038/nature10137.
17. Edwards JG, Faux SP, Plummer SM, Abrams KR, Walker RA, Waller DA, O’Byrne KJ. Cyclooxygenase-2 expression is a novel prognostic factor in malignant mesothelioma. Clin Cancer Res 8: 1857-1862, 2002.
18. Erzurum S, Rounds SI, Stevens T, Aldred M, Aliotta J, Archer SL, Asosingh K, Balaban R, Bauer N, Bhattacharya J, Bogaard H, Choudhary G, Dorn GW II, Dweik R, Fagan K, Fallon M, Finkel T, Geraci M, Gladwin MT, Hassoun PM, Humbert M, Kaminski N, Kawut SM, Loscalzo J, McDonald D, McMurtry IF, Newman J, Nicolls M, Rabinovitch M, Shizuru J, Oka M, Polgar P, Rodman D, Schumacker P, Stenmark K, Tuder R, Voelkel N, Sullivan E, Weinshilboum R, Yoder MC, Zhao Y, Gail D, Moore TM. Strategic plan for lung vascular research: an NHLBI-ORDR workshop report. Am J Respir Crit Care Med 182: 1554-1562, 2010. doi:10.1164/rccm.201006-0869WS.
19. Feng X, Liu P, Zhou X, Li MT, Li FL, Wang Z, Meng Z, Sun YP, Yu Y, Xiong Y, Yuan HX, Guan KL. Thromboxane A2 activates YAP/TAZ protein to induce vascular smooth muscle cell proliferation and migration. J Biol Chem 291: 18947-18958, 2016. doi:10.1074/jbc.M116.739722.
20. Fernández-Alvarez A, Llorente-Izquierdo C, Mayoral R, Agra N, Boscá L, Casado M, Martín-Sanz P. Evaluation of epigenetic modulation of cyclooxygenase-2 as a prognostic marker for hepatocellular carcinoma. Oncogenesis 1: e23, 2012. doi:10.1038/oncsis.2012.23.
21. Fredenburgh LE, Liang OD, Macias AA, Polte TR, Liu X, Riascos DF, Chung SW, Schissel SL, Ingber DE, Mitsialis SA, Kourembanas S, Perrella MA. Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells. Circulation 117: 2114-2122, 2008. doi:10.1161/CIRCULATIONAHA.107.716241.
22. Fredenburgh LE, Ma J, Perrella MA. Cyclooxygenase-2 inhibition and hypoxia-induced pulmonary hypertension: effects on pulmonary vascular remodeling and contractility. Trends Cardiovasc Med 19: 31-37, 2009. doi:10.1016/j.tcm.2009.04.003.
23. Gan CT, Lankhaar JW, Westerhof N, Marcus JT, Becker A, Twisk JW, Boonstra A, Postmus PE, Vonk-Noordegraaf A. Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension. Chest 132: 1906-1912, 2007. doi:10.1378/chest.07-1246.
24. Goncharov DA, Kudryashova TV, Ziai H, Ihida-Stansbury K, DeLisser H, Krymskaya VP, Tuder RM, Kawut SM, Goncharova EA. Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension. Circulation 129: 864-874, 2014. doi:10.1161/CIRCULATIONAHA.113.004581.
25. Guvendiren M, Perepelyuk M, Wells RG, Burdick JA. Hydrogels with differential and patterned mechanics to study stiffness-mediated myofibroblastic differentiation of hepatic stellate cells. J Mech Behav Biomed Mater 38: 198-208, 2014. doi:10.1016/j.jmbbm.2013.11.008.
26. Halder G, Dupont S, Piccolo S. Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat Rev Mol Cell Biol 13: 591-600, 2012. doi:10.1038/nrm3416.
27. Hsu BY, Bae YH, Mui KL, Liu SL, Assoian RK. Apolipoprotein E3 inhibits Rho to regulate the mechanosensitive expression of COX-2. PLoS One 10: e0128974, 2015. doi:10.1371/journal.pone.0128974.
28. Hunter KS, Lee PF, Lanning CJ, Ivy DD, Kirby KS, Claussen LR, Chan KC, Shandas R. Pulmonary vascular input impedance is a combined measure of pulmonary vascular resistance and stiffness and predicts clinical outcomes better than pulmonary vascular resistance alone in pediatric patients with pulmonary hypertension. Am Heart J 155: 166-174, 2008. doi:10.1016/j.ahj.2007.08.014.
29. Ilkiw R, Todorovich-Hunter L, Maruyama K, Shin J, Rabinovitch M. SC-39026, a serine elastase inhibitor, prevents muscularization of peripheral arteries, suggesting a mechanism of monocrotaline-induced pulmonary hypertension in rats. Circ Res 64: 814-825, 1989. doi:10.1161/01. RES.64.4.814.
30. Jing ZC, Parikh K, Pulido T, Jerjes-Sanchez C, White RJ, Allen R, Torbicki A, Xu KF, Yehle D, Laliberte K, Arneson C, Rubin LJ. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 127: 624-633, 2013. doi:10.1161/CIRCULATIONAHA.112.124388.
31. Kang KW, Chang HJ, Kim YJ, Choi BW, Lee HS, Yang WI, Shim CY, Ha J, Chung N. Cardiac magnetic resonance imaging-derived pulmonary artery distensibility index correlates with pulmonary artery stiffness and predicts functional capacity in patients with pulmonary arterial hypertension. Circ J 75: 2244-2251, 2011. doi:10.1253/circj.CJ-10-1310.
32. Kim M, Kim T, Johnson RL, Lim DS. Transcriptional co-repressor function of the hippo pathway transducers YAP and TAZ. Cell Reports 11:270-282, 2015. doi:10.1016/j.celrep.2015.03.015.
33. Kimura TE, Duggirala A, Smith MC, White S, Sala-Newby GB, Newby AC, Bond M. The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP. J Mol Cell Cardiol 90: 1-10, 2016. doi:10.1016/j.yjmcc.2015.11.024.
34. Klein EA, Yin L, Kothapalli D, Castagnino P, Byfield FJ, Xu T, Levental I, Hawthorne E, Janmey PA, Assoian RK. Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening. Curr Biol 19: 1511-1518, 2009. doi:10.1016/j.cub.2009.07.069.
35. Kömhoff M, Guan Y, Shappell HW, Davis L, Jack G, Shyr Y, Koch MO, Shappell SB, Breyer MD. Enhanced expression of cyclooxygenase-2 in high grade human transitional cell bladder carcinomas. Am J Pathol 157: 29-35, 2000. doi:10.1016/S0002-9440(10)64513-0.
36. Kudryashova TV, Goncharov DA, Pena A, Kelly N, Vanderpool R, Baust J, Kobir A, Shufesky W, Mora AL, Morelli AE, Zhao J, Ihida-Stansbury K, Chang B, DeLisser H, Tuder RM, Kawut SM, Silljé HH, Shapiro S, Zhao Y, Goncharova EA. Hippo-integrin-linked kinase cross-talk controls self-sustaining proliferation and survival in pulmonary hypertension. Am J Respir Crit Care Med 194: 866-877, 2016. doi:10.1164/rccm.201510-2003OC.
37. Kural MH, Billiar KL. Myofibroblast persistence with real-time changes in boundary stiffness. Acta Biomater 32: 223-230, 2016. doi:10.1016/j. actbio.2015.12.031.
38. Lalich JJ, Merkow L. Pulmonary arteritis produced in rat by feeding Crotalaria spectabilis. Lab Invest 10: 744-750, 1961.
39. Landt SG, Marinov GK, Kundaje A, Kheradpour P, Pauli F, Batzoglou S, Bernstein BE, Bickel P, Brown JB, Cayting P, Chen Y, DeSalvo G, Epstein C, Fisher-Aylor KI, Euskirchen G, Gerstein M, Gertz J, Hartemink AJ, Hoffman MM, Iyer VR, Jung YL, Karmakar S, Kellis M, Kharchenko PV, Li Q, Liu T, Liu XS, Ma L, Milosavljevic A, Myers RM, Park PJ, Pazin MJ, Perry MD, Raha D, Reddy TE, Rozowsky J, Shoresh N, Sidow A, Slattery M, Stamatoyannopoulos JA, Tolstorukov MY, White KP, Xi S, Farnham PJ, Lieb JD, Wold BJ, Snyder M. ChIP-seq guidelines and practices of the ENCODE and modENCODE consortia. Genome Res 22: 1813-1831, 2012. doi:10.1101/gr.136184.111.
40. Lang IM, Gaine SP. Recent advances in targeting the prostacyclin pathway in pulmonary arterial hypertension. Eur Respir Rev 24: 630-641, 2015. [Erratum. Eur Respir Rev 25: 99, 2016; Eur Respir Rev 26: 155067, 2017.] doi:10.1183/16000617.0067-2015.
41. Lankhaar JW, Westerhof N, Faes TJ, Gan CT, Marques KM, Boonstra A, van den Berg FG, Postmus PE, Vonk-Noordegraaf A. Pulmonary vascular resistance and compliance stay inversely related during treatment of pulmonary hypertension. Eur Heart J 29: 1688-1695, 2008. doi:10.1093/eurheartj/ehn103.
42. Lau EM, Chemla D, Godinas L, Zhu K, Sitbon O, Savale L, Montani D, Jaïs X, Celermajer DS, Simonneau G, Humbert M, Hervé P. Loss of vascular distensibility during exercise is an early hemodynamic marker of pulmonary vascular disease. Chest 149: 353-361, 2016. doi:10.1378/chest.15-0125.
43. Le VP, Stoka KV, Yanagisawa H, Wagenseil JE. Fibulin-5 null mice with decreased arterial compliance maintain normal systolic left ventricular function, but not diastolic function during maturation. Physiol Rep 2:e00257, 2014. doi:10.1002/phy2.257.
44. Lee H, Dellatore SM, Miller WM, Messersmith PB. Mussel-inspired surface chemistry for multifunctional coatings. Science 318: 426-430, 2007. doi:10.1126/science.1147241.
45. Li M, Scott DE, Shandas R, Stenmark KR, Tan W. High pulsatility flow induces adhesion molecule and cytokine mRNA expression in distal pulmonary artery endothelial cells. Ann Biomed Eng 37: 1082-1092, 2009. doi:10.1007/s10439-009-9684-3.
46. Li M, Tan Y, Stenmark KR, Tan W. High pulsatility flow induces acute endothelial inflammation through overpolarizing cells to activate NF-B. Cardiovasc Eng Technol 4: 26-38, 2013. doi:10.1007/s13239-012-0115-5.
47. Liu F, Haeger CM, Dieffenbach PB, Sicard D, Chrobak I, Coronata AM, Suárez Velandia MM, Vitali S, Colas RA, Norris PC, Marinković A, Liu X, Ma J, Rose CD, Lee SJ, Comhair SA, Erzurum SC, McDonald JD, Serhan CN, Walsh SR, Tschumperlin DJ, Fredenburgh LE. Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension. JCI Insight 1: e86987, 2016. doi:10.1172/jci.insight.86987.
48. Liu F, Lagares D, Choi KM, Stopfer L, Marinković A, Vrbanac V, Probst CK, Hiemer SE, Sisson TH, Horowitz JC, Rosas IO, Fredenburgh LE, Feghali-Bostwick C, Varelas X, Tager AM, Tschumperlin DJ. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Physiol Lung Cell Mol Physiol 308: L344-L357, 2015. doi:10.1152/ajplung.00300.2014.
49. Liu F, Mih JD, Shea BS, Kho AT, Sharif AS, Tager AM, Tschumperlin DJ. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. J Cell Biol 190: 693-706, 2010. doi:10.1083/jcb.201004082.
50. Ma H, Killaars AR, DelRio FW, Yang C, Anseth KS. Myofibroblastic activation of valvular interstitial cells is modulated by spatial variations in matrix elasticity and its organization. Biomaterials 131: 131-144, 2017. doi:10.1016/j.biomaterials.2017.03.040.
51. Mabry KM, Payne SZ, Anseth KS. Microarray analyses to quantify advantages of 2D and 3D hydrogel culture systems in maintaining the native valvular interstitial cell phenotype. Biomaterials 74: 31-41, 2016. doi:10.1016/j.biomaterials.2015.09.035.
52. Mahapatra S, Nishimura RA, Oh JK, McGoon MD. The prognostic value of pulmonary vascular capacitance determined by Doppler echocardiography in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr 19: 1045-1050, 2006. doi:10.1016/j.echo.2006.03.008.
53. Mahapatra S, Nishimura RA, Sorajja P, Cha S, McGoon MD. Relationship of pulmonary arterial capacitance and mortality in idiopathic pulmonary arterial hypertension. J Am Coll Cardiol 47: 799-803, 2006. doi:10.1016/j.jacc.2005.09.054.
54. Malenfant S, Neyron AS, Paulin R, Potus F, Meloche J, Provencher S, Bonnet S. Signal transduction in the development of pulmonary arterial hypertension. Pulm Circ 3: 278-293, 2013. doi:10.4103/2045-8932.114752.
55. Marinković A, Mih JD, Park JA, Liu F, Tschumperlin DJ. Improved throughput traction microscopy reveals pivotal role for matrix stiffness in fibroblast contractility and TGF-β responsiveness. Am J Physiol Lung Cell Mol Physiol 303: L169-L180, 2012. doi:10.1152/ajplung.00108.2012.
56. Maruyama K, Ye CL, Woo M, Venkatacharya H, Lines LD, Silver MM, Rabinovitch M. Chronic hypoxic pulmonary hypertension in rats and increased elastolytic activity. Am J Physiol 261: H1716-H1726, 1991.
57. Mih JD, Sharif AS, Liu F, Marinković A, Symer MM, Tschumperlin DJ. A multiwell platform for studying stiffness-dependent cell biology. PLoS One 6: e19929, 2011. doi:10.1371/journal.pone.0019929.
58. Nave AH, Mižíková I, Niess G, Steenbock H, Reichenberger F, Talavera ML, Veit F, Herold S, Mayer K, Vadász I, Weissmann N, Seeger W, Brinckmann J, Morty RE. Lysyl oxidases play a causal role in vascular remodeling in clinical and experimental pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 34: 1446-1458, 2014. doi:10.1161/ATVBAHA.114.303534.
59. Nickel NP, Spiekerkoetter E, Gu M, Li CG, Li H, Kaschwich M, Diebold I, Hennigs JK, Kim KY, Miyagawa K, Wang L, Cao A, Sa S, Jiang X, Stockstill RW, Nicolls MR, Zamanian RT, Bland RD, Rabinovitch M. Elafin reverses pulmonary hypertension via caveolin-1-dependent bone morphogenetic protein signaling. Am J Respir Crit Care Med 191: 1273-1286, 2015. doi:10.1164/rccm.201412-2291OC.
60. Pellegrini P, Rossi A, Pasotti M, Raineri C, Cicoira M, Bonapace S, Dini FL, Temporelli PL, Vassanelli C, Vanderpool R, Naeije R, Ghio S. Prognostic relevance of pulmonary arterial compliance in patients with chronic heart failure. Chest 145: 1064-1070, 2014. doi:10.1378/chest.13-1510.
61. Rashidian J, Le Scolan E, Ji X, Zhu Q, Mulvihill MM, Nomura D, Luo K. Ski regulates Hippo and TAZ signaling to suppress breast cancer progression. Sci Signal 8: ra14, 2015. doi:10.1126/scisignal.2005735.
62. Rodés-Cabau J, Domingo E, Román A, Majó J, Lara B, Padilla F, Anívarro I, Angel J, Tardif JC, Soler-Soler J. Intravascular ultrasound of the elastic pulmonary arteries: a new approach for the evaluation of primary pulmonary hypertension. Heart 89: 311-315, 2003. doi:10.1136/heart.89.3.311.
63. Sanz J, Kariisa M, Dellegrottaglie S, Prat-González S, Garcia MJ, Fuster V, Rajagopalan S. Evaluation of pulmonary artery stiffness in pulmonary hypertension with cardiac magnetic resonance. JACC Cardiovasc Imaging 2: 286-295, 2009. doi:10.1016/j.jcmg.2008.08.007.
64. Scott D, Tan Y, Shandas R, Stenmark KR, Tan W. High pulsatility flow stimulates smooth muscle cell hypertrophy and contractile protein expression. Am J Physiol Lung Cell Mol Physiol 304: L70-L81, 2013. doi:10.1152/ajplung.00342.2012.
65. Simonneau G, Torbicki A, Hoeper MM, Delcroix M, Karlócai K, Galiè N, Degano B, Bonderman D, Kurzyna M, Efficace M, Giorgino R, Lang IM. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J 40: 874-880, 2012. doi:10.1183/09031936.00137511.
66. Sitbon O, Vonk Noordegraaf A. Epoprostenol and pulmonary arterial hypertension: 20 years of clinical experience. Eur Respir Rev 26: 160055, 2017. doi:10.1183/16000617.0055-2016.
67. Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD, McLaughlin VV, Jessup M, Grizzle WE, Aldred MA, Cool CD, Tuder RM. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 186: 261-272, 2012. doi:10.1164/rccm.201201-0164OC.
68. Stevens GR, Garcia-Alvarez A, Sahni S, Garcia MJ, Fuster V, Sanz J. RV dysfunction in pulmonary hypertension is independently related to pulmonary artery stiffness. JACC Cardiovasc Imaging 5: 378-387, 2012. doi:10.1016/j.jcmg.2011.11.020.
69. Tan W, Madhavan K, Hunter KS, Park D, Stenmark KR. Vascular stiffening in pulmonary hypertension: cause or consequence? (2013 Grover Conference series). Pulm Circ 4: 560-580, 2014. doi:10.1086/677370.
70. Tan Y, Tseng PO, Wang D, Zhang H, Hunter K, Hertzberg J, Stenmark KR, Tan W. Stiffening-induced high pulsatility flow activates endothelial inflammation via a TLR2/NF-B pathway. PLoS One 9:e102195, 2014. doi:10.1371/journal.pone.0102195.
71. Tedford RJ, Hassoun PM, Mathai SC, Girgis RE, Russell SD, Thiemann DR, Cingolani OH, Mudd JO, Borlaug BA, Redfield MM, Lederer DJ, Kass DA. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation 125: 289-297, 2012. doi:10.1161/CIRCULATIONAHA.111.051540.
72. Thenappan T, Prins KW, Pritzker MR, Scandurra J, Volmers K, Weir EK. The critical role of pulmonary arterial compliance in pulmonary hypertension. Ann Am Thorac Soc 13: 276-284, 2016. doi:10.1513/AnnalsATS.201509-599FR.
73. Todorovich-Hunter L, Dodo H, Ye C, McCready L, Keeley FW, Rabinovitch M. Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease. Am Rev Respir Dis 146: 213-223, 1992. doi:10.1164/ajrccm/146.1.213.
74. Tuder RM, Archer SL, Dorfmüller P, Erzurum SC, Guignabert C, Michelakis E, Rabinovitch M, Schermuly R, Stenmark KR, Morrell NW. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 62, Suppl: D4-D12, 2013. doi:10.1016/j.jacc.2013.10.025.
75. Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, Badesch D, Voelkel NF. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 159: 1925-1932, 1999. doi:10.1164/ajrccm.159.6.9804054.
76. Vachiéry JL. Prostacyclins in pulmonary arterial hypertension: the need for earlier therapy. Adv Ther 28: 251-269, 2011. doi:10.1007/s12325-011-0005-5.
77. Ventetuolo CE, Gabler NB, Fritz JS, Smith KA, Palevsky HI, Klinger JR, Halpern SD, Kawut SM. Are hemodynamics surrogate end points in pulmonary arterial hypertension? Circulation 130: 768-775, 2014. doi:10.1161/CIRCULATIONAHA.114.009690.
78. Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, Newman J, Oudiz RJ, Provencher S, Torbicki A, Voelkel NF, Hassoun PM. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol 62, Suppl:D22-D33, 2013. doi:10.1016/j.jacc.2013.10.027.
79. Wang H, Haeger SM, Kloxin AM, Leinwand LA, Anseth KS. Redirecting valvular myofibroblasts into dormant fibroblasts through lightmediated reduction in substrate modulus. PLoS One 7: e39969, 2012. doi:10.1371/journal.pone.0039969.
80. Wang H, Tibbitt MW, Langer SJ, Leinwand LA, Anseth KS. Hydrogels preserve native phenotypes of valvular fibroblasts through an elasticity-regulated PI3K/AKT pathway. Proc Natl Acad Sci USA 110: 19336-19341, 2013. doi:10.1073/pnas.1306369110.
81. Wang X, Hu G, Gao X, Wang Y, Zhang W, Harmon EY, Zhi X, Xu Z, Lennartz MR, Barroso M, Trebak M, Chen C, Zhou J. The induction of yes-associated protein expression after arterial injury is crucial for smooth muscle phenotypic modulation and neointima formation. Arterioscler Thromb Vasc Biol 32: 2662-2669, 2012. doi:10.1161/ATVBAHA.112.254730.
82. Wang Y, Hu G, Liu F, Wang X, Wu M, Schwarz JJ, Zhou J. Deletion of yes-associated protein (YAP) specifically in cardiac and vascular smooth muscle cells reveals a crucial role for YAP in mouse cardiovascular development. Circ Res 114: 957-965, 2014. doi:10.1161/CIRCRESAHA.114.303411.
83. Wang Z, Chesler NC. Pulmonary vascular wall stiffness: An important contributor to the increased right ventricular afterload with pulmonary hypertension. Pulm Circ 1: 212-223, 2011. doi:10.4103/2045-8932.83453.
84. Ye CL, Rabinovitch M. Inhibition of elastolysis by SC-37698 reduces development and progression of monocrotaline pulmonary hypertension. Am J Physiol 261: H1255-H1267, 1991.
85. Zaidi SH, You XM, Ciura S, Husain M, Rabinovitch M. Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation 105: 516-521, 2002. doi:10.1161/hc0402.102866.
86. Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B, Rosato A, Bicciato S, Cordenonsi M, Piccolo S. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol 17: 1218-1227, 2015. doi:10.1038/ncb3216.
87. Zhang H, Liu CY, Zha ZY, Zhao B, Yao J, Zhao S, Xiong Y, Lei QY, Guan KL. TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition. J Biol Chem 284: 13355-13362, 2009. doi:10.1074/jbc.M900843200.
88. Zhang W, Nandakumar N, Shi Y, Manzano M, Smith A, Graham G, Gupta S, Vietsch EE, Laughlin SZ, Wadhwa M, Chetram M, Joshi M, Wang F, Kallakury B, Toretsky J, Wellstein A, Yi C. Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Sci Signal 7: ra42, 2014. doi:10.1126/scisignal.2005049.
89. Zhao B, Ye X, Yu J, Li L, Li W, Li S, Yu J, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, Guan KL. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 22: 1962-1971, 2008. doi:10.1101/gad.1664408.