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Cellular and Molecular Processes in Pulmonary Hypertension

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Lung Inflammation in Health and Disease, Volume II

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1304))

Abstract

Pulmonary hypertension (PH) is a progressive lung disease characterized by persistent pulmonary vasoconstriction. Another well-recognized characteristic of PH is the muscularization of peripheral pulmonary arteries. This pulmonary vasoremodeling manifests in medial hypertrophy/hyperplasia of smooth muscle cells (SMCs) with possible neointimal formation. The underlying molecular processes for these two major vascular responses remain not fully understood. On the other hand, a series of very recent studies have shown that the increased reactive oxygen species (ROS) seems to be an important player in mediating pulmonary vasoconstriction and vasoremodeling, thereby leading to PH. Mitochondria are a primary site for ROS production in pulmonary artery (PA) SMCs, which subsequently activate NADPH oxidase to induce further ROS generation, i.e., ROS-induced ROS generation. ROS control the activity of multiple ion channels to induce intracellular Ca2+ release and extracellular Ca2+ influx (ROS-induced Ca2+ release and influx) to cause PH. ROS and Ca2+ signaling may synergistically trigger an inflammatory cascade to implicate in PH. Accordingly, this paper explores the important roles of ROS, Ca2+, and inflammatory signaling in the development of PH, including their reciprocal interactions, key molecules, and possible therapeutic targets.

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Abbreviations

ACE:

Angiotensin-converting enzyme

Ang II:

Angiotensin II

Apaf1:

Apoptotic protease-activating factor 1

AT1:

Angiotensin II type 1 receptor

ATP:

Adenosine triphosphate

Bax:

Bcl-2-like protein

CaMKII:

Calcium/calmodulin kinase II

CaSR:

Calcium sensing receptor

Cav:

Voltage-dependent Ca2+ channel

c-MYC:

Proto-oncogene encoding bHLH transcription factor protein

Coenzyme Q:

Ubiquinol-cytochrome c reductase

Cyt:

Cytochrome

DAG:

1,2-Diacylglycerol

DNA:

Deoxyribonucleic acid

DRP1:

Dynamin-related protein 1

Duox:

Dual oxidase

ER:

Endoplasmic reticulum

ETC:

Electron transport chain

FAD:

Flavin adenine dinucleotide

Gpx1:

Glutathione peroxidase 1

HIF-1:

Hypoxia-inducible factor 1

HUVEC:

Human umbilical vein endothelial cells

ICAM-1:

Intercellular adhesion molecule 1

IP3(R):

Inositol 1,4,5-trisphosphate (receptor)

KV:

Voltage-dependent potassium channel

LDL:

Low-density lipoprotein

MCP-1:

Monocyte chemoattractant protein

mPTP:

Mitochondrial permeability transition pore

mRNA:

Messenger ribonucleic acid

NADH:

Nicotinamide adenine dinucleotide

NADPH:

Nicotinamide adenine dinucleotide phosphate

NOX:

NADPH oxidase

PASMCs:

Pulmonary artery smooth muscle cells

PDK1:

Gene coding for pyruvate dehydrogenase kinase 1

PH:

Pulmonary hypertension

PHD:

Prolyl hydroxylase

PKCε:

Protein kinase C epsilon

PLC:

Phospholipase C

RISP:

Rieske iron-sulfur protein

RNAi:

RNA interference

ROS:

Reactive oxygen species

RyR:

Ryanodine receptor

siRNA:

Small interfering RNA

Smad3:

Gene coding for Smad protein, transducers for TGF-β

SOD:

Superoxide dismutase

SR:

Sarcoplasmic reticulum

TGF-β:

Transforming growth factor beta

TRPC:

Transient receptor potential cation channels

VEGF(R):

Vascular endothelial growth factor (receptor)

References

  1. Benza RL, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164–72.

    Article  PubMed  Google Scholar 

  2. Adesina SE, et al. Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension. Free Radic Biol Med. 2015;87:36–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Aggarwal S, Gross CM, Sharma S, Fineman JR, Black SM. Reactive oxygen species in pulmonary vascular remodeling. Compr Physiol. 2013;3:1011–34.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cao JY, Wales KM, Cordina R, Lau EMT, Celermajer DS. Pulmonary vasodilator therapies are of no benefit in pulmonary hypertension due to left heart disease: a meta-analysis. Int J Cardiol. 2018;273:213–20.

    Article  PubMed  Google Scholar 

  5. Spiekerkoetter E, Kawut SM, de Jesus Perez VA. New and emerging therapies for pulmonary arterial hypertension. Annu Rev Med. 2019;70:45–59.

    Article  CAS  PubMed  Google Scholar 

  6. Suresh K, Shimoda LA. Endothelial cell reactive oxygen species and Ca(2+) signaling in pulmonary hypertension. Adv Exp Med Biol. 2017;967:299–314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rathore R, et al. Hypoxia activates NADPH oxidase to increase [ROS]i and [Ca2+]i through the mitochondrial ROS-PKCepsilon signaling axis in pulmonary artery smooth muscle cells. Free Radic Biol Med. 2008;45:1223–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang L, et al. Reactive oxygen species effect PASMCs apoptosis via regulation of dynamin-related protein 1 in hypoxic pulmonary hypertension. Histochem Cell Biol. 2016;146:71–84.

    Article  CAS  PubMed  Google Scholar 

  9. Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82:47–95.

    Article  CAS  PubMed  Google Scholar 

  10. Phaniendra A, Jestadi DB, Periyasamy L. Free radicals: properties, sources, targets, and their implication in various diseases. Indian J Clin Biochem. 2015;30:11–26.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang J, et al. ROS and ROS-mediated cellular signaling. Oxidative Med Cell Longev. 2016;2016:4350965.

    Article  Google Scholar 

  12. Fridovich I. Superoxide anion radical (O2-.), superoxide dismutases, and related matters. J Biol Chem. 1997;272:18515–7.

    Article  CAS  PubMed  Google Scholar 

  13. Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol. 2000;279:L1005–28.

    Article  CAS  PubMed  Google Scholar 

  14. Paravicini TM, Touyz RM. NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities. Diabetes Care. 2008;31(Suppl 2):S170–80.

    Article  CAS  PubMed  Google Scholar 

  15. Wilcox CS, et al. Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Natl Acad Sci U S A. 1992;89:11993–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. MacMicking JD, et al. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell. 1995;81:641–50.

    Article  CAS  PubMed  Google Scholar 

  17. Wang YX, Zheng YM. ROS-dependent signaling mechanisms for hypoxic Ca(2+) responses in pulmonary artery myocytes. Antioxid Redox Signal. 2010;12:611–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Archer SL, Huang J, Henry T, Peterson D, Weir EK. A redox-based O2 sensor in rat pulmonary vasculature. Circ Res. 1993;73:1100–12.

    Article  CAS  PubMed  Google Scholar 

  19. Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003;552:335–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Michelakis ED, et al. Diversity in mitochondrial function explains differences in vascular oxygen sensing. Circ Res. 2002;90:1307–15.

    Article  CAS  PubMed  Google Scholar 

  21. Waypa GB, Chandel NS, Schumacker PT. Model for hypoxic pulmonary vasoconstriction involving mitochondrial oxygen sensing. Circ Res. 2001;88:1259–66.

    Article  CAS  PubMed  Google Scholar 

  22. Waypa GB, et al. Increases in mitochondrial reactive oxygen species trigger hypoxia-induced calcium responses in pulmonary artery smooth muscle cells. Circ Res. 2006;99:970–8.

    Article  CAS  PubMed  Google Scholar 

  23. Waypa GB, et al. Mitochondrial reactive oxygen species trigger calcium increases during hypoxia in pulmonary arterial myocytes. Circ Res. 2002;91:719–26.

    Article  CAS  PubMed  Google Scholar 

  24. Rathore R, et al. Mitochondrial ROS-PKCepsilon signaling axis is uniquely involved in hypoxic increase in [Ca2+]i in pulmonary artery smooth muscle cells. Biochem Biophys Res Commun. 2006;351:784–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang X, et al. A mechanism underlying hypertensive occurrence in the metabolic syndrome: cooperative effect of oxidative stress and calcium accumulation in vascular smooth muscle cells. Horm Metab Res. 2014;46:126–32.

    CAS  PubMed  Google Scholar 

  26. Vanden Hoek TL, Becker LB, Shao Z, Li C, Schumacker PT. Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes. J Biol Chem. 1998;273:18092–8.

    Article  Google Scholar 

  27. Kajiya M, et al. Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive rats. Am J Physiol Heart Circ Physiol. 2007;292:H2737–44.

    Article  CAS  PubMed  Google Scholar 

  28. Matoba T, Shimokawa H. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. J Pharmacol Sci. 2003;92:1–6.

    Article  CAS  PubMed  Google Scholar 

  29. Touyz RM, et al. Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res. 2002;90:1205–13.

    Article  CAS  PubMed  Google Scholar 

  30. Lacy F, Kailasam MT, O’Connor DT, Schmid-Schonbein GW, Parmer RJ. Plasma hydrogen peroxide production in human essential hypertension: role of heredity, gender, and ethnicity. Hypertension. 2000;36:878–84.

    Article  CAS  PubMed  Google Scholar 

  31. Diebold BA, Bokoch GM. Molecular basis for Rac2 regulation of phagocyte NADPH oxidase. Nat Immunol. 2001;2:211–5.

    Article  CAS  PubMed  Google Scholar 

  32. Geiszt M, Kopp JB, Varnai P, Leto TL. Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci U S A. 2000;97:8010–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mittal M, et al. Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res. 2007;101:258–67.

    Article  CAS  PubMed  Google Scholar 

  34. Matsuno K, et al. Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice. Circulation. 2005;112:2677–85.

    Article  CAS  PubMed  Google Scholar 

  35. Chen F, Haigh S, Barman S, Fulton DJ. From form to function: the role of Nox4 in the cardiovascular system. Front Physiol. 2012;3:412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Martyn KD, Frederick LM, von Loehneysen K, Dinauer MC, Knaus UG. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal. 2006;18:69–82.

    Article  CAS  PubMed  Google Scholar 

  37. Nisimoto Y, Jackson HM, Ogawa H, Kawahara T, Lambeth JD. Constitutive NADPH-dependent electron transferase activity of the Nox4 dehydrogenase domain. Biochemistry. 2010;49:2433–42.

    Article  CAS  PubMed  Google Scholar 

  38. Ago T, et al. Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes. Circ Res. 2010;106:1253–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kuroda J, et al. NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc Natl Acad Sci U S A. 2010;107:15565–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Baines CP, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature. 2005;434:658–62.

    Article  CAS  PubMed  Google Scholar 

  41. Anilkumar N, Weber R, Zhang M, Brewer A, Shah AM. Nox4 and nox2 NADPH oxidases mediate distinct cellular redox signaling responses to agonist stimulation. Arterioscler Thromb Vasc Biol. 2008;28:1347–54.

    Article  CAS  PubMed  Google Scholar 

  42. Basuroy S, Bhattacharya S, Leffler CW, Parfenova H. Nox4 NADPH oxidase mediates oxidative stress and apoptosis caused by TNF-alpha in cerebral vascular endothelial cells. Am J Physiol Cell Physiol. 2009;296:C422–32.

    Article  CAS  PubMed  Google Scholar 

  43. Cucoranu I, et al. NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res. 2005;97:900–7.

    Article  CAS  PubMed  Google Scholar 

  44. Hwang J, et al. Pulsatile versus oscillatory shear stress regulates NADPH oxidase subunit expression: implication for native LDL oxidation. Circ Res. 2003;93:1225–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lu X, Murphy TC, Nanes MS, Hart CM. PPAR{gamma} regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-{kappa}B. Am J Physiol Lung Cell Mol Physiol. 2010;299:L559–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pedruzzi E, et al. NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol Cell Biol. 2004;24:10703–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rajagopalan S, et al. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest. 1996;97:1916–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sorescu D, et al. Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation. 2002;105:1429–35.

    Article  CAS  PubMed  Google Scholar 

  49. Griffith B, et al. NOX enzymes and pulmonary disease. Antioxid Redox Signal. 2009;11:2505–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang M, et al. NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis. Proc Natl Acad Sci U S A. 2010;107:18121–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chandel NS, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem. 2000;275:25130–8.

    Article  CAS  PubMed  Google Scholar 

  52. Dengler VL, Galbraith M, Espinosa JM. Transcriptional regulation by hypoxia inducible factors. Crit Rev Biochem Mol Biol. 2014;49:1–15.

    Article  CAS  PubMed  Google Scholar 

  53. Fijalkowska I, et al. Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol. 2010;176:1130–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lei W, et al. Expression and analyses of the HIF-1 pathway in the lungs of humans with pulmonary arterial hypertension. Mol Med Rep. 2016;14:4383–90.

    Article  CAS  PubMed  Google Scholar 

  55. Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148:399–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12:5447–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417:1–13.

    Article  CAS  PubMed  Google Scholar 

  58. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5:343–54.

    Article  CAS  PubMed  Google Scholar 

  59. Hirota K. Hypoxia-inducible factor 1, a master transcription factor of cellular hypoxic gene expression. J Anesth. 2002;16:150–9.

    Article  PubMed  Google Scholar 

  60. Okamoto A, et al. HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death. Sci Rep. 2017;7:3816.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Aragones J, et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet. 2008;40:170–80.

    Article  CAS  PubMed  Google Scholar 

  62. Ziello JE, Jovin IS, Huang Y. Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med. 2007;80:51–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3:177–85.

    Article  PubMed  CAS  Google Scholar 

  64. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006;3:187–97.

    Article  CAS  PubMed  Google Scholar 

  65. Fukuda R, et al. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007;129:111–22.

    Article  CAS  PubMed  Google Scholar 

  66. Zhang H, et al. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell. 2007;11:407–20.

    Article  CAS  PubMed  Google Scholar 

  67. Hoffman B, Liebermann DA. Apoptotic signaling by c-MYC. Oncogene. 2008;27:6462–72.

    Article  CAS  PubMed  Google Scholar 

  68. Eskes R, et al. Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions. J Cell Biol. 1998;143:217–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Guzy RD, Schumacker PT. Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia. Exp Physiol. 2006;91:807–19.

    Article  CAS  PubMed  Google Scholar 

  70. Carmeliet P, et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998;394:485–90.

    Article  CAS  PubMed  Google Scholar 

  71. Laderoute KR, et al. 5′-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol Cell Biol. 2006;26:5336–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sanhueza C, et al. The twisted survivin connection to angiogenesis. Mol Cancer. 2015;14:198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Voelkel NF, Vandivier RW, Tuder RM. Vascular endothelial growth factor in the lung. Am J Physiol Lung Cell Mol Physiol. 2006;290:L209–21.

    Article  CAS  PubMed  Google Scholar 

  74. Hirose S, Hosoda Y, Furuya S, Otsuki T, Ikeda E. Expression of vascular endothelial growth factor and its receptors correlates closely with formation of the plexiform lesion in human pulmonary hypertension. Pathol Int. 2000;50:472–9.

    Article  CAS  PubMed  Google Scholar 

  75. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.

    Article  CAS  PubMed  Google Scholar 

  76. Olofsson B, et al. Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc Natl Acad Sci U S A. 1998;95:11709–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Park JE, Chen HH, Winer J, Houck KA, Ferrara N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem. 1994;269:25646–54.

    Article  CAS  PubMed  Google Scholar 

  78. Ashikari-Hada S, Habuchi H, Kariya Y, Kimata K. Heparin regulates vascular endothelial growth factor165-dependent mitogenic activity, tube formation, and its receptor phosphorylation of human endothelial cells. Comparison of the effects of heparin and modified heparins. J Biol Chem. 2005;280:31508–15.

    Article  CAS  PubMed  Google Scholar 

  79. Chen TT, et al. Anchorage of VEGF to the extracellular matrix conveys differential signaling responses to endothelial cells. J Cell Biol. 2010;188:595–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mahabeleshwar GH, Feng W, Reddy K, Plow EF, Byzova TV. Mechanisms of integrin-vascular endothelial growth factor receptor cross-activation in angiogenesis. Circ Res. 2007;101:570–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hellstrom M, Phng LK, Gerhardt H. VEGF and Notch signaling: the yin and yang of angiogenic sprouting. Cell Adhes Migr. 2007;1:133–6.

    Article  Google Scholar 

  82. Thomas JL, et al. Interactions between VEGFR and Notch signaling pathways in endothelial and neural cells. Cell Mol Life Sci. 2013;70:1779–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhuang G, et al. Phosphoproteomic analysis implicates the mTORC2-FoxO1 axis in VEGF signaling and feedback activation of receptor tyrosine kinases. Sci Signal. 2013;6:ra25.

    Article  PubMed  CAS  Google Scholar 

  84. Claesson-Welsh L. VEGF receptor signal transduction – a brief update. Vasc Pharmacol. 2016;86:14–7.

    Article  CAS  Google Scholar 

  85. Guo D, Wang Q, Li C, Wang Y, Chen X. VEGF stimulated the angiogenesis by promoting the mitochondrial functions. Oncotarget. 2017;8:77020–7.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Partovian C, et al. Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am J Respir Cell Mol Biol. 2000;23:762–71.

    Article  CAS  PubMed  Google Scholar 

  87. Farkas L, et al. VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats. J Clin Invest. 2009;119:1298–311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhang Z, Neiva KG, Lingen MW, Ellis LM, Nor JE. VEGF-dependent tumor angiogenesis requires inverse and reciprocal regulation of VEGFR1 and VEGFR2. Cell Death Differ. 2010;17:499–512.

    Article  CAS  PubMed  Google Scholar 

  89. Meng L, et al. Survivin is critically involved in VEGFR2 signaling-mediated esophageal cancer cell survival. Biomed Pharmacother. 2018;107:139–45.

    Article  CAS  PubMed  Google Scholar 

  90. McMurtry MS, et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest. 2005;115:1479–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rai PR, et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178:558–64.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Nicolls MR, et al. New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis. Pulm Circ. 2012;2:434–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Taraseviciene-Stewart 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. FASEB J. 2001;15:427–38.

    Article  CAS  PubMed  Google Scholar 

  94. Montani D, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125:2128–37.

    Article  CAS  PubMed  Google Scholar 

  95. Taegtmeyer H, Sen S, Vela D. Return to the fetal gene program: a suggested metabolic link to gene expression in the heart. Ann N Y Acad Sci. 2010;1188:191–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Jonassen AK, Mjos OD, Sack MN. p70s6 kinase is a functional target of insulin activated Akt cell-survival signaling. Biochem Biophys Res Commun. 2004;315:160–5.

    Article  CAS  PubMed  Google Scholar 

  97. Sack MN, Yellon DM. Insulin therapy as an adjunct to reperfusion after acute coronary ischemia: a proposed direct myocardial cell survival effect independent of metabolic modulation. J Am Coll Cardiol. 2003;41:1404–7.

    Article  CAS  PubMed  Google Scholar 

  98. Yang R, Smolders I, Dupont AG. Blood pressure and renal hemodynamic effects of angiotensin fragments. Hypertens Res. 2011;34:674–83.

    Article  CAS  PubMed  Google Scholar 

  99. de Man FS, et al. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:780–9.

    Article  PubMed  CAS  Google Scholar 

  100. Peach MJ. Renin-angiotensin system: biochemistry and mechanisms of action. Physiol Rev. 1977;57:313–70.

    Article  CAS  PubMed  Google Scholar 

  101. Schelling JR, Nkemere N, Konieczkowski M, Martin KA, Dubyak GR. Angiotensin II activates the beta 1 isoform of phospholipase C in vascular smooth muscle cells. Am J Phys. 1997;272:C1558–66.

    Article  CAS  Google Scholar 

  102. Rohacs T. Regulation of transient receptor potential channels by the phospholipase C pathway. Adv Biol Regul. 2013;53:341–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Song T, Hao Q, Zheng YM, Liu QH, Wang YX. Inositol 1,4,5-trisphosphate activates TRPC3 channels to cause extracellular Ca2+ influx in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2015;309:L1455–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Numata T, Kiyonaka S, Kato K, Takahashi N, Mori Y. In Zhu MX, editors. TRP Channels. Boca Raton, FL, 2011.

    Google Scholar 

  105. Hughes AR, Putney JW Jr. Inositol phosphate formation and its relationship to calcium signaling. Environ Health Perspect. 1990;84:141–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Liu Z, Khalil RA. Evolving mechanisms of vascular smooth muscle contraction highlight key targets in vascular disease. Biochem Pharmacol. 2018;153:91–122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Collier ML, Ji G, Wang Y, Kotlikoff MI. Calcium-induced calcium release in smooth muscle: loose coupling between the action potential and calcium release. J Gen Physiol. 2000;115:653–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74:1141–8.

    Article  CAS  PubMed  Google Scholar 

  109. Marsboom G, 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;110:1484–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ikeda Y, et al. Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res. 2015;116:264–78.

    Article  CAS  PubMed  Google Scholar 

  111. Hu C, Huang Y, Li L. Drp1-dependent mitochondrial fission plays critical roles in physiological and pathological progresses in mammals. Int J Mol Sci. 2017;18:144.

    Article  PubMed Central  CAS  Google Scholar 

  112. Shirakabe A, et al. Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure. Circulation. 2016;133:1249–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Wan YY, et al. Involvement of Drp1 in hypoxia-induced migration of human glioblastoma U251 cells. Oncol Rep. 2014;32:619–26.

    Article  PubMed  Google Scholar 

  114. Suen DF, Norris KL, Youle RJ. Mitochondrial dynamics and apoptosis. Genes Dev. 2008;22:1577–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hanson CJ, Bootman MD, Roderick HL. Cell signalling: IP3 receptors channel calcium into cell death. Curr Biol. 2004;14:R933–5.

    Article  CAS  PubMed  Google Scholar 

  116. Karbowski M, et al. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol. 2002;159:931–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Westphal D, Kluck RM, Dewson G. Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis. Cell Death Differ. 2014;21:196–205.

    Article  CAS  PubMed  Google Scholar 

  118. Dewson G, Kluck RM. Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. J Cell Sci. 2009;122:2801–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Thomas KJ, Jacobson MR. Defects in mitochondrial fission protein dynamin-related protein 1 are linked to apoptotic resistance and autophagy in a lung cancer model. PLoS One. 2012;7:e45319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Warnholtz A, et al. Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation. 1999;99:2027–33.

    Article  CAS  PubMed  Google Scholar 

  121. Violi F, Basili S, Nigro C, Pignatelli P. Role of NADPH oxidase in atherosclerosis. Futur Cardiol. 2009;5:83–92.

    Article  CAS  Google Scholar 

  122. Gordeeva AV, Zvyagilskaya RA, Labas YA. Cross-talk between reactive oxygen species and calcium in living cells. Biochemistry (Mosc). 2003;68:1077–80.

    Article  CAS  Google Scholar 

  123. Sag CM, Wagner S, Maier LS. Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. Free Radic Biol Med. 2013;63:338–49.

    Article  CAS  PubMed  Google Scholar 

  124. Zimmerman MC, et al. Activation of NADPH oxidase 1 increases intracellular calcium and migration of smooth muscle cells. Hypertension. 2011;58:446–53.

    Article  CAS  PubMed  Google Scholar 

  125. Rowell J, Koitabashi N, Kass DA. TRP-ing up heart and vessels: canonical transient receptor potential channels and cardiovascular disease. J Cardiovasc Transl Res. 2010;3:516–24.

    Article  PubMed  Google Scholar 

  126. Rodman DM, et al. The low-voltage-activated calcium channel CAV3.1 controls proliferation of human pulmonary artery myocytes. Chest. 2005;128:581S–2S.

    Article  CAS  PubMed  Google Scholar 

  127. Rodman DM, et al. Low-voltage-activated (T-type) calcium channels control proliferation of human pulmonary artery myocytes. Circ Res. 2005;96:864–72.

    Article  CAS  PubMed  Google Scholar 

  128. Li GW, et al. The calcium-sensing receptor mediates hypoxia-induced proliferation of rat pulmonary artery smooth muscle cells through MEK1/ERK1,2 and PI3K pathways. Basic Clin Pharmacol Toxicol. 2011;108:185–93.

    Article  CAS  PubMed  Google Scholar 

  129. Yamamura A, et al. Enhanced Ca(2+)-sensing receptor function in idiopathic pulmonary arterial hypertension. Circ Res. 2012;111:469–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Monteith GR, Kable EP, Chen S, Roufogalis BD. Plasma membrane calcium pump-mediated calcium efflux and bulk cytosolic free calcium in cultured aortic smooth muscle cells from spontaneously hypertensive and Wistar-Kyoto normotensives rats. J Hypertens. 1996;14:435–42.

    Article  CAS  PubMed  Google Scholar 

  131. Wray S, Burdyga T. Sarcoplasmic reticulum function in smooth muscle. Physiol Rev. 2010;90:113–78.

    Article  CAS  PubMed  Google Scholar 

  132. Kourie JI. Interaction of reactive oxygen species with ion transport mechanisms. Am J Phys. 1998;275:C1–24.

    Article  CAS  Google Scholar 

  133. Zima AV, Blatter LA. Redox regulation of cardiac calcium channels and transporters. Cardiovasc Res. 2006;71:310–21.

    Article  CAS  PubMed  Google Scholar 

  134. Truong L, Zheng YM, Wang YX. Mitochondrial Rieske iron-sulfur protein in pulmonary artery smooth muscle: a key primary signaling molecule in pulmonary hypertension. Arch Biochem Biophys. 2020;683:108234.

    Article  CAS  PubMed  Google Scholar 

  135. Cornea RL, Nitu FR, Samso M, Thomas DD, Fruen BR. Mapping the ryanodine receptor FK506-binding protein subunit using fluorescence resonance energy transfer. J Biol Chem. 2010;285:19219–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Firth AL, Yuill KH, Smirnov SV. Mitochondria-dependent regulation of Kv currents in rat pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2008;295:L61–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Rizzuto R, et al. Ca(2+) transfer from the ER to mitochondria: when, how and why. Biochim Biophys Acta. 2009;1787:1342–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Gorlach A, Bertram K, Hudecova S, Krizanova O. Calcium and ROS: a mutual interplay. Redox Biol. 2015;6:260–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Webster KA. Mitochondrial membrane permeabilization and cell death during myocardial infarction: roles of calcium and reactive oxygen species. Futur Cardiol. 2012;8:863–84.

    Article  CAS  Google Scholar 

  140. Chaube R, Werstuck GH. Mitochondrial ROS versus ER ROS: which comes first in myocardial calcium dysregulation? Front Cardiovasc Med. 2016;3:36.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Song T, Zheng YM, Wang YX. Cross talk between mitochondrial reactive oxygen species and sarcoplasmic reticulum calcium in pulmonary arterial smooth muscle cells. Adv Exp Med Biol. 2017;967:289–98.

    Article  CAS  PubMed  Google Scholar 

  142. Korde AS, Yadav VR, Zheng YM, Wang YX. Primary role of mitochondrial Rieske iron-sulfur protein in hypoxic ROS production in pulmonary artery myocytes. Free Radic Biol Med. 2011;50:945–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kawanami D, et al. Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine-endothelial cell interactions. Biochem Biophys Res Commun. 2004;314:415–9.

    Article  CAS  PubMed  Google Scholar 

  144. Vozarova de Courten B, Degawa-Yamauchi M, Considine RV, Tataranni PA. High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians. Diabetes. 2004;53:1279–84.

    Article  CAS  PubMed  Google Scholar 

  145. Raghuraman G, Zuniga MC, Yuan H, Zhou W. PKCepsilon mediates resistin-induced NADPH oxidase activation and inflammation leading to smooth muscle cell dysfunction and intimal hyperplasia. Atherosclerosis. 2016;253:29–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Reddy S, et al. Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure. Physiol Genomics. 2012;44:562–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Potus F, et al. Downregulation of MicroRNA-126 contributes to the failing right ventricle in pulmonary arterial hypertension. Circulation. 2015;132:932–43.

    Article  CAS  PubMed  Google Scholar 

  148. Bockmeyer CL, et al. Plexiform vasculopathy of severe pulmonary arterial hypertension and microRNA expression. J Heart Lung Transplant. 2012;31:764–72.

    Article  PubMed  Google Scholar 

  149. Caruso P, 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;30:716–23.

    Article  CAS  PubMed  Google Scholar 

  150. Drake JI, et al. Molecular signature of a right heart failure program in chronic severe pulmonary hypertension. Am J Respir Cell Mol Biol. 2011;45:1239–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Shi L, et al. miR-223-IGF-IR signalling in hypoxia- and load-induced right-ventricular failure: a novel therapeutic approach. Cardiovasc Res. 2016;111:184–93.

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. Vic Maietta, Jorge Reyes-García and Vishal R. Yadav contributed equally with all other contributors.

Authors and Affiliations

  1. Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA

    Vic Maietta, Jorge Reyes-García, Vishal R. Yadav, Yun-Min Zheng & Yong-Xiao Wang

  2. Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico

    Jorge Reyes-García

  3. Department of Medical Physiology, College of Medicine, Texas A&M University, College Station, TX, USA

    Xu Peng

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  1. Vic Maietta
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  3. Vishal R. Yadav
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  4. Yun-Min Zheng
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Correspondence to Yun-Min Zheng , Xu Peng or Yong-Xiao Wang .

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    Yong-Xiao Wang

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Maietta, V., Reyes-García, J., Yadav, V.R., Zheng, YM., Peng, X., Wang, YX. (2021). Cellular and Molecular Processes in Pulmonary Hypertension. In: Wang, YX. (eds) Lung Inflammation in Health and Disease, Volume II. Advances in Experimental Medicine and Biology, vol 1304. Springer, Cham. https://doi.org/10.1007/978-3-030-68748-9_2

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