Skip to main content
SpringerLink
Log in

Cell-to-Cell Crosstalk: A New Insight into Pulmonary Hypertension

  • Chapter
  • First Online:
Reviews of Physiology, Biochemistry and Pharmacology

Part of the book series: Reviews of Physiology, Biochemistry and Pharmacology ((REVIEWS,volume 184))

Abstract

Pulmonary hypertension (PH) is a disease with high pulmonary arterial pressure, pulmonary vasoconstriction, pulmonary vascular remodeling, and microthrombosis in complex plexiform lesions, but it has been unclear of the exact mechanism of PH. A new understanding of the pathogenesis of PH is occurred and focused on the role of crosstalk between the cells on pulmonary vessels and pulmonary alveoli. It was found that the crosstalks among the endothelial cells, smooth muscle cells, fibroblasts, pericytes, alveolar epithelial cells, and macrophages play important roles in cell proliferation, migration, inflammation, and so on. Therefore, the heterogeneity of multiple pulmonary blood vessels and alveolar cells and tracking the transmitters of cell communication could be conducive to the further insights into the pathogenesis of PH to discover the potential therapeutic targets for PH.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

15-HETE:

15-Hydroxyeicosatetraenoic acid

5-HTT:

Serotonin transporter

5-LO:

5-Lipoxygenase

AASMCs:

Aortic artery smooth cells

ADAM17:

A disintegrin and metalloproteinase 17

AECs:

Alveolar epithelial cells

AKT:

Protein kinase B

AT1:

Alveolar type I

AT2:

Alveolar type II

BMPR2:

Bone morphogenic protein receptor 2

C/EBPβ:

CCAAT/enhancer-binding protein beta

CCR2:

C-C chemokine receptor types 2

CCR5:

C-C chemokine receptor types 5

CTGF:

Connective tissue growth factor

CXCL1:

Murine chemokine 1

CXCL12:

Chemokine 12

CXCL8:

Chemokine 8

Ecs:

Endothelial cells

EGFR:

Epidermal growth factor receptor

EndoMT:

Endothelial-to mesenchymal transition

ERK:

Extracellular signal-regulated kinase

ERK1/2:

Signal-regulated kinase 1/2

ET-1:

Endothelin-1

FoxM1:

Forkhead box M1

FOXO3a:

Forkhead box protein O3a

GM-CSF:

Granulocyte macrophage colony-stimulating factor

GSK-3β:

Glycogen synthase kinase-3β

H2O2:

Hydrogen peroxide

HIF1α:

Hypoxia-inducible factor-1alpha

HIMF:

Hypoxia-induced mitogenic factor

HIV:

Human immunodeficiency virus

HMGB1:

High mobility group box 1

hPAH:

Hereditary pulmonary arterial hypertension

HPH:

Hypoxic pulmonary hypertension

IL-6:

Interleukin 6

IL-8:

Interleukin 8

ILK:

Integrin-linked kinase

IPF:

Idiopathic pulmonary fibrosis

JAK2:

Janus kinase 2

LTB4:

Leukotriene B4

LVEF:

Left ventricular ejection fraction

MIF:

Macrophage migration inhibitory factor

MiR-143:

microRNA-143

MiR-92a-3p:

microRNA-92a-3p

MMP-2:

Matrix metalloproteinase-2

MMP-9:

Matrix metalloproteinase-9

mPAP:

Mean pulmonary artery pressure

NF-κB:

Nuclear factor-Κb

Notch1:

Notch receptor 1

Nox4:

NADPH oxidase 4

NRGs:

Neuregulins

OPN:

Osteopontin

p38MAPK:

p38 mitogen-activated protein kinases

PAECs:

Pulmonary artery endothelial cells

PAH:

Pulmonary arterial hypertension

PASMCs:

Pulmonary artery smooth muscle cells

PCH:

Pulmonary capillary hemangiomatosis

PDGF-B:

Platelet-derived growth factor BB

PDK4:

Pyruvate dehydrogenase kinase 4

PFKFB3:

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3

PI3K:

Phosphatidylinositol-3-kinase

PMVECs:

Pulmonary microvascular endothelial cells

PS1:

Presenilin 1

PTEN:

Phosphatase and tensin homolog

PVOD:

Pulmonary veno-occlusive disease

RAGE:

Receptor for advanced glycation end products

ROS:

Reactive oxygen species

Shh:

Sonic hedgehog

SMCs:

Smooth muscle cells

SOD2:

Superoxide dismutase 2

Stamp2:

Six-transmembrane protein of prostate 2

STAT3:

Transcription 3

TGFα:

Transforming growth factor-alpha

TNF-α:

Tumor necrosis factor-alpha

TSP1:

The secreted protein thrombospondin 1

Wnt5a:

Wnt family member 5A

WSPH:

World symposium on pulmonary hypertension

References

  • Abid S, Marcos E, Parpaleix A, Amsellem V, Breau M, Houssaini A, Vienney N, Lefevre M, Derumeaux G, Evans S, Hubeau C, Delcroix M, Quarck R, Adnot S, Lipskaia L (2019) CCR2/CCR5-mediated macrophage-smooth muscle cell crosstalk in pulmonary hypertension. Eur Respir J 54(4):1802308

    Article  Google Scholar 

  • Awad KS, Elinoff JM, Wang S, Gairhe S, Ferreyra GA, Cai R, Sun J, Solomon MA, Danner RL (2016) Raf/ERK drives the proliferative and invasive phenotype of BMPR2-silenced pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol 310(2):L187–L201

    Article  Google Scholar 

  • Bai P, Lyu L, Yu T, Zuo C, Fu J, He Y, Wan Q, Wan N, Jia D, Lyu A (2019) Macrophage-derived legumain promotes pulmonary hypertension by activating the MMP (matrix metalloproteinase)-2/TGF (transforming growth factor)-β1 signaling. Arterioscler Thromb Vasc Biol 39(4):e130–e145

    Article  CAS  Google Scholar 

  • Batool M, Berghausen EM, Zierden M, Vantler M, Schermuly RT, Baldus S, Rosenkranz S, Ten Freyhaus H (2020) The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice. Basic Res Cardiol 115(6):68

    Article  CAS  Google Scholar 

  • Böger R, Hannemann J (2020) Dual role of the L-arginine-ADMA-NO pathway in systemic hypoxic vasodilation and pulmonary hypoxic vasoconstriction. Pulm Circ 10(2):2045894020918850

    Google Scholar 

  • Bordenave J, Thuillet R, Tu L, Phan C, Cumont A, Marsol C, Huertas A, Savale L, Hibert M, Galzi J-L, Bonnet D, Humbert M, Frossard N, Guignabert C (2020) Neutralization of CXCL12 attenuates established pulmonary hypertension in rats. Cardiovasc Res 116(3):686–697

    Article  CAS  Google Scholar 

  • Byrne AJ, Maher TM, Lloyd CM (2016) Pulmonary macrophages: a new therapeutic pathway in fibrosing lung disease? Trends Mol Med 22(4):303–316

    Article  CAS  Google Scholar 

  • Chan SY, Loscalzo J (2008) Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol 44(1):14–30

    Article  CAS  Google Scholar 

  • Chen Q, Liu Y (2020) Heterogeneous groups of alveolar type II cells in lung homeostasis and repair. Am J Physiol Cell Physiol 319(6):C991–C996

    Article  CAS  Google Scholar 

  • Chen S, Rong M, Platteau A, Hehre D, Smith H, Ruiz P, Whitsett J, Bancalari E, Wu S (2011) CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 300(3):L330–L340

    Article  CAS  Google Scholar 

  • Dai Z, Li M, Wharton J, Zhu MM, Zhao Y-Y (2016) Prolyl-4 hydroxylase 2 (PHD2) deficiency in endothelial cells and hematopoietic cells induces obliterative vascular remodeling and severe pulmonary arterial hypertension in mice and humans through hypoxia-inducible factor-2α. Circulation 133(24):2447–2458

    Article  CAS  Google Scholar 

  • Dai Z, Zhu MM, Peng Y, Jin H, Machireddy N, Qian Z, Zhang X, Zhao Y-Y (2018) Endothelial and smooth muscle cell interaction via FoxM1 signaling mediates vascular remodeling and pulmonary hypertension. Am J Respir Crit Care Med 198(6):788–802

    Article  CAS  Google Scholar 

  • Deng L, Blanco FJ, Stevens H, Lu R, Caudrillier A, McBride M, McClure JD, Grant J, Thomas M, Frid M, Stenmark K, White K, Seto AG, Morrell NW, Bradshaw AC, MacLean MR, Baker AH (2015) MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension. Circ Res 117(10):870–883

    Article  CAS  Google Scholar 

  • Dickinson MG, Bartelds B, Molema G, Borgdorff MA, Boersma B, Takens J, Weij M, Wichers P, Sietsma H, Berger RMF (2011) Egr-1 expression during neointimal development in flow-associated pulmonary hypertension. Am J Pathol 179(5):2199–2209

    Article  CAS  Google Scholar 

  • Dreymueller D, Martin C, Schumacher J, Groth E, Boehm JK, Reiss LK, Uhlig S, Ludwig A (2014) Smooth muscle cells relay acute pulmonary inflammation via distinct ADAM17/ErbB axes. J Immunol 192(2):722–731

    Article  CAS  Google Scholar 

  • El Kasmi KC, Pugliese SC, Riddle SR, Poth JM, Anderson AL, Frid MG, Li M, Pullamsetti SS, Savai R, Nagel MA, Fini MA, Graham BB, Tuder RM, Friedman JE, Eltzschig HK, Sokol RJ, Stenmark KR (2014) Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension. J Immunol 193(2):597–609

    Article  Google Scholar 

  • Evans CE, Cober ND, Dai Z, Stewart DJ, Zhao Y-Y (2021) Endothelial cells in the pathogenesis of pulmonary arterial hypertension. Eur Respir J 58(3):2003957

    Article  CAS  Google Scholar 

  • Fiscon G, Conte F, Farina L, Paci P (2018) Network-based approaches to explore complex biological systems towards network medicine. Genes 9(9):437

    Article  Google Scholar 

  • Gao Y, Chen T, Raj JU (2016) Endothelial and smooth muscle cell interactions in the pathobiology of pulmonary hypertension. Am J Respir Cell Mol Biol 54(4):451–460

    Article  CAS  Google Scholar 

  • Grimmer B, Kuebler WM (2017) The endothelium in hypoxic pulmonary vasoconstriction. J Appl Physiol (1985) 123(6):1635–1646

    Article  CAS  Google Scholar 

  • Gu J, Zhang H, Ji B, Jiang H, Zhao T, Jiang R, Zhang Z, Tan S, Ahmed A, Gu Y (2017) Vesicle miR-195 derived from endothelial cells inhibits expression of serotonin transporter in vessel smooth muscle cells. Sci Rep 7:43546

    Article  Google Scholar 

  • Guignabert C, Tu L, Girerd B, Ricard N, Huertas A, Montani D, Humbert M (2015) New molecular targets of pulmonary vascular remodeling in pulmonary arterial hypertension: importance of endothelial communication. Chest 147(2):529–537

    Article  Google Scholar 

  • Hansmann G (2017) Pulmonary hypertension in infants, children, and young adults. J Am Coll Cardiol 69(20):2551–2569

    Article  Google Scholar 

  • Hoeper MM, Ghofrani H-A, Grünig E, Klose H, Olschewski H, Rosenkranz S (2017) Pulmonary hypertension. Dtsch Arzteblatt Int 114(5):73–84

    Google Scholar 

  • Hou J, Ji J, Chen X, Cao H, Tan Y, Cui Y, Xiang Z, Han X (2021) Alveolar epithelial cell-derived sonic hedgehog promotes pulmonary fibrosis through OPN-dependent alternative macrophage activation. FEBS J 288(11):3530–3546

    Article  CAS  Google Scholar 

  • Hough RF, Bhattacharya S, Bhattacharya J (2018) Crosstalk signaling between alveoli and capillaries. Pulm Circ 8(3):2045894018783735

    Article  Google Scholar 

  • Hsu JY, Major JL, Riching AS, Sen R, Pires da Silva J, Bagchi RA (2020) Beyond the genome: challenges and potential for epigenetics-driven therapeutic approaches in pulmonary arterial hypertension. Biochem Cell Biol = Biochim Biol Cell 98(6):631–646

    Article  CAS  Google Scholar 

  • Huang S, Yue Y, Feng K, Huang X, Li H, Hou J, Yang S, Huang S, Liang M, Chen G, Wu Z (2020) Conditioned medium from M2b macrophages modulates the proliferation, migration, and apoptosis of pulmonary artery smooth muscle cells by deregulating the PI3K/Akt/FoxO3a pathway. PeerJ 8:e9110

    Article  Google Scholar 

  • Huertas A, Perros F, Tu L, Cohen-Kaminsky S, Montani D, Dorfmüller P, Guignabert C, Humbert M (2014) Immune dysregulation and endothelial dysfunction in pulmonary arterial hypertension: a complex interplay. Circulation 129(12):1332–1340

    Article  Google Scholar 

  • Hwang I (2013) Cell-cell communication via extracellular membrane vesicles and its role in the immune response. Mol Cells 36(2):105–111

    Article  CAS  Google Scholar 

  • Jiao Y, Li Z, Loughran PA, Fan EK, Scott MJ, Li Y, Billiar TR, Wilson MA, Shi X, Fan J (2018) Frontline science: macrophage-derived exosomes promote neutrophil necroptosis following hemorrhagic shock. J Leukoc Biol 103(2):175–183

    CAS  Google Scholar 

  • Jimenez SA, Piera-Velazquez S (2016) Endothelial to mesenchymal transition (EndoMT) in the pathogenesis of systemic sclerosis-associated pulmonary fibrosis and pulmonary arterial hypertension. Myth or reality? Matrix Biol 51:26–36

    Article  CAS  Google Scholar 

  • Kato A, Okura T, Hamada C, Miyoshi S, Katayama H, Higaki J, Ito R (2014) Cell stress induces upregulation of osteopontin via the ERK pathway in type II alveolar epithelial cells. PLoS One 9(6):e100106

    Article  Google Scholar 

  • Kim D, George MP (2019) Pulmonary hypertension. Med Clin North Am 103(3):413–423

    Article  Google Scholar 

  • Kuebler WM, Bonnet S, Tabuchi A (2018) Inflammation and autoimmunity in pulmonary hypertension: is there a role for endothelial adhesion molecules? (2017 Grover conference series). Pulm Circ 8(2):2045893218757596

    Article  Google Scholar 

  • Labrousse-Arias D, Castillo-González R, Rogers NM, Torres-Capelli M, Barreira B, Aragonés J, Cogolludo Á, Isenberg JS, Calzada MJ (2016) HIF-2α-mediated induction of pulmonary thrombospondin-1 contributes to hypoxia-driven vascular remodelling and vasoconstriction. Cardiovasc Res 109(1):115–130

    Article  CAS  Google Scholar 

  • Larson-Casey JL, He C, Carter AB (2020) Mitochondrial quality control in pulmonary fibrosis. Redox Biol 33:101426

    Article  CAS  Google Scholar 

  • Le Hiress M, Tu L, Ricard N, Phan C, Thuillet R, Fadel E, Dorfmüller P, Montani D, de Man F, Humbert M, Huertas A, Guignabert C (2015) Proinflammatory signature of the dysfunctional endothelium in pulmonary hypertension. Role of the macrophage migration inhibitory factor/CD74 complex. Am J Respir Crit Care Med 192(8):983–997

    Article  Google Scholar 

  • Lee J, Arisi I, Puxeddu E, Mramba LK, Amicosante M, Swaisgood CM, Pallante M, Brantly ML, Sköld CM, Saltini C (2018) Bronchoalveolar lavage (BAL) cells in idiopathic pulmonary fibrosis express a complex pro-inflammatory, pro-repair, angiogenic activation pattern, likely associated with macrophage iron accumulation. PLoS One 13(4):e0194803

    Article  Google Scholar 

  • Li S, Zhai C, Shi W, Feng W, Xie X, Pan Y, Wang J, Yan X, Chai L, Wang Q, Zhang Q, Liu P, Li M (2020) Leukotriene B induces proliferation of rat pulmonary arterial smooth muscle cells via modulating GSK-3β/β-catenin pathway. Eur J Pharmacol 867:172823

    Article  CAS  Google Scholar 

  • Li M, Riddle S, Kumar S, Poczobutt J, McKeon BA, Frid MG, Ostaff M, Reisz JA, Nemkov T, Fini MA, Laux A, Hu C-J, El Kasmi KC, D'Alessandro A, Brown RD, Zhang H, Stenmark KR (2021) Microenvironmental regulation of macrophage transcriptomic and metabolomic profiles in pulmonary hypertension. Front Immunol 12:640718

    Article  CAS  Google Scholar 

  • Liang L-Y, Wang M-M, Liu M, Zhao W, Wang X, Shi L, Zhu M-J, Zhao Y-L, Liu L, Maurya P, Wang Y (2020) Chronic toxicity of methamphetamine: oxidative remodeling of pulmonary arteries. Toxicol In Vitro 62:104668

    Article  Google Scholar 

  • Lin Q, Fan C, Gomez-Arroyo J, Van Raemdonck K, Meuchel LW, Skinner JT, Everett AD, Fang X, Macdonald AA, Yamaji-Kegan K, Johns RA (2019) HIMF (hypoxia-induced mitogenic factor) signaling mediates the HMGB1 (high mobility group box 1)-dependent endothelial and smooth muscle cell crosstalk in pulmonary hypertension. Arterioscler Thromb Vasc Biol 39(12):2505–2519

    Article  CAS  Google Scholar 

  • Liu Y, Zhang H, Yan L, Du W, Zhang M, Chen H, Zhang L, Li G, Li J, Dong Y, Zhu D (2018) MMP-2 and MMP-9 contribute to the angiogenic effect produced by hypoxia/15-HETE in pulmonary endothelial cells. J Mol Cell Cardiol 121:36–50

    Article  Google Scholar 

  • Liu F, Peng W, Chen J, Xu Z, Jiang R, Shao Q, Zhao N, Qian K (2021) Exosomes derived from alveolar epithelial cells promote alveolar macrophage activation mediated by miR-92a-3p in sepsis-induced acute lung injury. Front Cell Infect Microbiol 11:646546

    Article  CAS  Google Scholar 

  • Makino A, Firth AL, Yuan JXJ (2011) Endothelial and smooth muscle cell ion channels in pulmonary vasoconstriction and vascular remodeling. Compr Physiol 1(3):1555–1602

    Article  Google Scholar 

  • Miyagawa K, Shi M, Chen P-I, Hennigs JK, Zhao Z, Wang M, Li CG, Saito T, Taylor S, Sa S, Cao A, Wang L, Snyder MP, Rabinovitch M (2019) Smooth muscle contact drives endothelial regeneration by BMPR2-Notch1-mediated metabolic and epigenetic changes. Circ Res 124(2):211–224

    Article  CAS  Google Scholar 

  • Montani D, Lau EM, Dorfmüller P, Girerd B, Jaïs X, Savale L, Perros F, Nossent E, Garcia G, Parent F, Fadel E, Soubrier F, Sitbon O, Simonneau G, Humbert M (2016) Pulmonary veno-occlusive disease. Eur Respir J 47(5):1518–1534

    Article  Google Scholar 

  • Mumby S, Gambaryan N, Meng C, Perros F, Humbert M, Wort SJ, Adcock IM (2017) Bromodomain and extra-terminal protein mimic JQ1 decreases inflammation in human vascular endothelial cells: implications for pulmonary arterial hypertension. Respirology 22(1):157–164

    Article  Google Scholar 

  • Napoli C, Benincasa G, Loscalzo J (2019) Epigenetic inheritance underlying pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 39(4):653–664

    Article  CAS  Google Scholar 

  • Oliveira SDS, Castellon M, Chen J, Bonini MG, Gu X, Elliott MH, Machado RF, Minshall RD (2017) Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGF-β-driven pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 312(5):L760–L771

    Article  Google Scholar 

  • Pasha Q (2014) Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: genetics of pulmonary hypertension. Ann Thorac Med 9(Suppl 1):S16–S20

    Article  Google Scholar 

  • Perros F, Ranchoux B, Izikki M, Bentebbal S, Happé C, Antigny F, Jourdon P, Dorfmüller P, Lecerf F, Fadel E, Simonneau G, Humbert M, Bogaard HJ, Eddahibi S (2015) Nebivolol for improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function in pulmonary hypertension. J Am Coll Cardiol 65(7):668–680

    Article  CAS  Google Scholar 

  • Peters-Golden M, Henderson WR (2007) Leukotrienes. N Engl J Med 357(18):1841–1854

    Article  CAS  Google Scholar 

  • Petrusca DN, Van Demark M, Gu Y, Justice MJ, Rogozea A, Hubbard WC, Petrache I (2014) Smoking exposure induces human lung endothelial cell adaptation to apoptotic stress. Am J Respir Cell Mol Biol 50(3):513–525

    Article  Google Scholar 

  • Pi L, Fu C, Lu Y, Zhou J, Jorgensen M, Shenoy V, Lipson KE, Scott EW, Bryant AJ (2018) Vascular endothelial cell-specific connective tissue growth factor (CTGF) is necessary for development of chronic hypoxia-induced pulmonary hypertension. Front Physiol 9:138

    Article  Google Scholar 

  • Pu X, Lin X, Duan X, Wang J, Shang J, Yun H, Chen Z (2020) Oxidative and endoplasmic reticulum stress responses to chronic high-altitude exposure during the development of high-altitude pulmonary hypertension. High Alt Med Biol 21(4):378–387

    Article  CAS  Google Scholar 

  • Pulido T, Zayas N, de Mendieta MA, Plascencia K, Escobar J (2016) Medical therapies for pulmonary arterial hypertension. Heart Fail Rev 21(3):273–283

    Article  CAS  Google Scholar 

  • Qian J, Tian W, Jiang X, Tamosiuniene R, Sung YK, Shuffle EM, Tu AB, Valenzuela A, Jiang S, Zamanian RT, Fiorentino DF, Voelkel NF, Peters-Golden M, Stenmark KR, Chung L, Rabinovitch M, Nicolls MR (2015) Leukotriene B4 activates pulmonary artery adventitial fibroblasts in pulmonary hypertension. Hypertension 66(6):1227–1239

    Article  CAS  Google Scholar 

  • Rafikova O, Al Ghouleh I, Rafikov R (2019) Focus on early events: pathogenesis of pulmonary arterial hypertension development. Antioxid Redox Signal 31(13):933–953

    Article  CAS  Google Scholar 

  • Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, Sattler C, Fadel E, Seferian A, Montani D, Dorfmüller P, Humbert M, Guignabert C (2014) Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation 129(15):1586–1597

    Article  CAS  Google Scholar 

  • Sawada H, Saito T, Nickel NP, Alastalo T-P, Glotzbach JP, Chan R, Haghighat L, Fuchs G, Januszyk M, Cao A, Lai Y-J, Perez VJ, Kim Y-M, Wang L, Chen P-I, Spiekerkoetter E, Mitani Y, Gurtner GC, Sarnow P, Rabinovitch M (2014) Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. J Exp Med 211(2):263–280

    Article  CAS  Google Scholar 

  • Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R (2019) Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 53(1):1801913

    Article  CAS  Google Scholar 

  • Southgate L, Machado RD, Gräf S, Morrell NW (2020) Molecular genetic framework underlying pulmonary arterial hypertension. Nat Rev Cardiol 17(2):85–95

    Article  CAS  Google Scholar 

  • Steffes LC, Froistad AA, Andruska A, Boehm M, McGlynn M, Zhang F, Zhang W, Hou D, Tian X, Miquerol L, Nadeau K, Metzger RJ, Spiekerkoetter E, Kumar ME (2020) A Notch3-marked subpopulation of vascular smooth muscle cells is the cell of origin for occlusive pulmonary vascular lesions. Circulation 142(16):1545–1561

    Article  CAS  Google Scholar 

  • Stenmark KR, Frid MG, Graham BB, Tuder RM (2018) Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension. Cardiovasc Res 114(4):551–564

    Article  CAS  Google Scholar 

  • Strauss B, Sassi Y, Bueno-Beti C, Ilkan Z, Raad N, Cacheux M, Bisserier M, Turnbull IC, Kohlbrenner E, Hajjar RJ, Hadri L, Akar FG (2019) Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension. J Mol Cell Cardiol 127:20–30

    Article  CAS  Google Scholar 

  • Thenappan T, Chan SY, Weir EK (2018) Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 315(5):H1322–H1331

    Article  CAS  Google Scholar 

  • Tian W, Jiang X, Tamosiuniene R, Sung YK, Qian J, Dhillon G, Gera L, Farkas L, Rabinovitch M, Zamanian RT, Inayathullah M, Fridlib M, Rajadas J, Peters-Golden M, Voelkel NF, Nicolls MR (2013) Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci Transl Med 5(200):200ra117

    Article  Google Scholar 

  • Tian W, Jiang X, Sung YK, Shuffle E, Wu T-H, Kao PN, Tu AB, Dorfmüller P, Cao A, Wang L, Peng G, Kim Y, Zhang P, Chappell J, Pasupneti S, Dahms P, Maguire P, Chaib H, Zamanian R, Peters-Golden M, Snyder MP, Voelkel NF, Humbert M, Rabinovitch M, Nicolls MR (2019) Phenotypically silent bone morphogenetic protein receptor 2 mutations predispose rats to inflammation-induced pulmonary arterial hypertension by enhancing the risk for neointimal transformation. Circulation 140(17):1409–1425

    Article  CAS  Google Scholar 

  • Tliba O, Panettieri RA (2009) Noncontractile functions of airway smooth muscle cells in asthma. Annu Rev Physiol 71:509–535

    Article  CAS  Google Scholar 

  • Tuder RM (2017) Pulmonary vascular remodeling in pulmonary hypertension. Cell Tissue Res 367(3):643–649

    Article  Google Scholar 

  • Udjus C, Cero FT, Halvorsen B, Behmen D, Carlson CR, Bendiksen BA, Espe EKS, Sjaastad I, Løberg EM, Yndestad A, Aukrust P, Christensen G, Skjønsberg OH, Larsen K-O (2019) Caspase-1 induces smooth muscle cell growth in hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 316(6):L999–L1012

    Article  CAS  Google Scholar 

  • Van Hung T, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Suzuki Y, Hirata K-i (2014) Inhibition of vascular endothelial growth factor receptor under hypoxia causes severe, human-like pulmonary arterial hypertension in mice: potential roles of interleukin-6 and endothelin. Life Sci 118(2):313–328

    Article  Google Scholar 

  • Voelkel NF, Gomez-Arroyo J, Abbate A, Bogaard HJ, Nicolls MR (2012) Pathobiology of pulmonary arterial hypertension and right ventricular failure. Eur Respir J 40(6):1555–1565

    Article  CAS  Google Scholar 

  • Wang R-S, Loscalzo J (2021) Network module-based drug repositioning for pulmonary arterial hypertension. CPT Pharmacometrics Syst Pharmacol 10(9):994–1005

    Article  CAS  Google Scholar 

  • Wang Y, Kuai Q, Gao F, Wang Y, He M, Zhou H, Han G, Jiang X, Ren S, Yu Q (2019) Overexpression of TIM-3 in macrophages aggravates pathogenesis of pulmonary fibrosis in mice. Am J Respir Cell Mol Biol 61(6):727–736

    Article  CAS  Google Scholar 

  • Wang X, Liu M, Zhu M-J, Shi L, Liu L, Zhao Y-L, Cheng L, Gu Y-J, Zhou M-Y, Chen L, Kumar A, Wang Y (2020) Resveratrol protects the integrity of alveolar epithelial barrier via SIRT1/PTEN/p-Akt pathway in methamphetamine-induced chronic lung injury. Cell Prolif 53(3):e12773

    Article  Google Scholar 

  • Wang Y, Li X, Niu W, Chen J, Zhang B, Zhang X, Wang Y, Dang S, Li Z (2021) The alveolar epithelial cells are involved in pulmonary vascular remodeling and constriction of hypoxic pulmonary hypertension. Respir Res 22(1):134

    Article  Google Scholar 

  • Xue C, Sowden M, Berk BC (2017) Extracellular cyclophilin A, especially acetylated, causes pulmonary hypertension by stimulating endothelial apoptosis, redox stress, and inflammation. Arterioscler Thromb Vasc Biol 37(6):1138–1146

    Article  CAS  Google Scholar 

  • Yeo Y, Yi ES, Kim J-M, Jo E-K, Seo S, Kim R-I, Kim KL, Sung J-H, Park SG, Suh W (2020) FGF12 (fibroblast growth factor 12) inhibits vascular smooth muscle cell remodeling in pulmonary arterial hypertension. Hypertension 76(6):1778–1786

    Article  CAS  Google Scholar 

  • Young LR, Gulleman PM, Short CW, Tanjore H, Sherrill T, Qi A, McBride AP, Zaynagetdinov R, Benjamin JT, Lawson WE, Novitskiy SV, Blackwell TS (2016) Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome. JCI Insight 1(17):e88947

    Article  Google Scholar 

  • Yuan K, Shao N-Y, Hennigs JK, Discipulo M, Orcholski ME, Shamskhou E, Richter A, Hu X, Wu JC, de Jesus Perez VA (2016) Increased pyruvate dehydrogenase kinase 4 expression in lung pericytes is associated with reduced endothelial-pericyte interactions and small vessel loss in pulmonary arterial hypertension. Am J Pathol 186(9):2500–2514

    Article  CAS  Google Scholar 

  • Yuan K, Shamskhou EA, Orcholski ME, Nathan A, Reddy S, Honda H, Mani V, Zeng Y, Ozen MO, Wang L, Demirci U, Tian W, Nicolls MR, de Jesus Perez VA (2019) Loss of endothelium-derived Wnt5a is associated with reduced pericyte recruitment and small vessel loss in pulmonary arterial hypertension. Circulation 139(14):1710–1724

    Article  CAS  Google Scholar 

  • Zhang C, Zhu X, Hua Y, Zhao Q, Wang K, Zhen L, Wang G, Lü J, Luo A, Cho WC, Lin X, Yu Z (2019) YY1 mediates TGF-β1-induced EMT and pro-fibrogenesis in alveolar epithelial cells. Respir Res 20(1):249

    Article  Google Scholar 

  • Zhao Q, Song P, Zou M-H (2021) AMPK and pulmonary hypertension: crossroads between vasoconstriction and vascular remodeling. Front Cell Dev Biol 9:691585

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by National Natural Science Foundation of China (No. 81973404, 81503058), Department of Education of Liaoning Province (No. JC2019034).

Declaration of Competing Interest: The authors declare that there are no competing interests.

Author Contributions: All authors contributed to the study conception and design. The first draft of the manuscript was written by Yan Zhang, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, People’s Republic of China

    Yan Zhang & Yun Wang

Authors
  1. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yun Wang .

Editor information

Editors and Affiliations

  1. Department of Biology, University of Copenhagen, Copenhagen, Denmark

    Stine Helene Falsig Pedersen

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Zhang, Y., Wang, Y. (2022). Cell-to-Cell Crosstalk: A New Insight into Pulmonary Hypertension. In: Pedersen, S.H.F. (eds) Reviews of Physiology, Biochemistry and Pharmacology. Reviews of Physiology, Biochemistry and Pharmacology, vol 184. Springer, Cham. https://doi.org/10.1007/112_2022_70

Download citation

Publish with us

Policies and ethics

Search

Navigation