1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Physiology
  4. Volume 87, 2025
  5. Article

Annual Review of Physiology

Volume 87, 2025

Specialized Pulmonary Vascular Cells in Development and Disease

Abstract

Endothelial cells (ECs) develop organ-specific gene expression and function in response to signals from the surrounding tissue. In turn, ECs can affect organ development and morphogenesis and promote or hinder disease response. In the lung, ECs play an essential role in gas exchange with the external environment, requiring both a close physical connection and a strong axis of communication with alveolar epithelial cells. A complete picture of the composition of the pulmonary endothelium is therefore critical for a full understanding of development, maintenance, and repair of the gas exchange interface. Defining the factors that control lung-specific EC specification, establish EC heterogeneity within the lung, and promote the differing contributions of EC subtypes to development, health, and disease will facilitate the development of much-needed regenerative therapies. This includes targeting therapeutics directly to ECs, developing pluripotent or primary cell–derived ECs to replace damaged or diseased vasculature, and vascularizing engineered tissues for transplant.

Keyword(s): lung development, lung progenitors, lung regeneration, lung stem cells, pulmonary endothelium, regenerative medicine
Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-022724-105226
2025-02-10
2025-04-22
Loading full text...

Full text loading...

/deliver/fulltext/physiol/87/1/annurev-physiol-022724-105226.html?itemId=/content/journals/10.1146/annurev-physiol-022724-105226&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Potente M, Mäkinen T. 2017.. Vascular heterogeneity and specialization in development and disease. . Nat. Rev. Mol. Cell Biol. 18:(8):477–94
     [Crossref] [Google Scholar]
  2. 2.
    Augustin HG, Koh GY. 2017.. Organotypic vasculature: from descriptive heterogeneity to functional pathophysiology. . Science 357:(6353):eaal2379
     [Crossref] [Google Scholar]
  3. 3.
    Sweeney MD, Sagare AP, Zlokovic BV. 2018.. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. . Nat. Rev. Neurol. 14:(3):133–50
     [Crossref] [Google Scholar]
  4. 4.
    Aird WC. 2012.. Endothelial cell heterogeneity. . Cold Spring Harb. Perspect. Med. 2:(1):a006429
     [Crossref] [Google Scholar]
  5. 5.
    Dumas SJ, Meta E, Borri M, Luo Y, Li X, et al. 2021.. Phenotypic diversity and metabolic specialization of renal endothelial cells. . Nat. Rev. Nephrol. 17:(7):441–64
     [Crossref] [Google Scholar]
  6. 6.
    Shetty S, Lalor PF, Adams DH. 2018.. Liver sinusoidal endothelial cells—gatekeepers of hepatic immunity. . Nat. Rev. Gastroenterol. Hepatol. 15:(9):555–67
     [Crossref] [Google Scholar]
  7. 7.
    Gomez-Salinero JM, Itkin T, Rafii S. 2021.. Developmental angiocrine diversification of endothelial cells for organotypic regeneration. . Dev. Cell 56:(22):3042–51
     [Crossref] [Google Scholar]
  8. 8.
    Reed HO, Wang L, Sonett J, Chen M, Yang J, et al. 2019.. Lymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damage. . J. Clin. Investig. 129:(6):2514–26
     [Crossref] [Google Scholar]
  9. 9.
    Aird WC. 2007.. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. . Circ. Res. 100:(2):158–73
     [Crossref] [Google Scholar]
  10. 10.
    Aird WC. 2007.. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. . Circ. Res. 100:(2):174–90
     [Crossref] [Google Scholar]
  11. 11.
    Nolan DJ, Ginsberg M, Israely E, Palikuqi B, Poulos MG, et al. 2013.. Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration. . Dev. Cell 26:(2):204–19
     [Crossref] [Google Scholar]
  12. 12.
    Ramasamy SK, Kusumbe AP, Adams RH. 2015.. Regulation of tissue morphogenesis by endothelial cell-derived signals. . Trends Cell Biol. 25:(3):148–57
     [Crossref] [Google Scholar]
  13. 13.
    Paik DT, Tian L, Williams IM, Rhee S, Zhang H, et al. 2020.. Single-cell RNA sequencing unveils unique transcriptomic signatures of organ-specific endothelial cells. . Circulation 142:(19):1848–62
     [Crossref] [Google Scholar]
  14. 14.
    Dumas SJ, Meta E, Borri M, Goveia J, Rohlenova K, et al. 2020.. Single-cell RNA sequencing reveals renal endothelium heterogeneity and metabolic adaptation to water deprivation. . J. Am. Soc. Nephrol. 31:(1):118–38
     [Crossref] [Google Scholar]
  15. 15.
    He L, Vanlandewijck M, Mäe MA, Andrae J, Ando K, et al. 2018.. Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types. . Sci. Data 5::180160
     [Crossref] [Google Scholar]
  16. 16.
    Kalucka J, de Rooij LPMH, Goveia J, Rohlenova K, Dumas SJ, et al. 2020.. Single-cell transcriptome atlas of murine endothelial cells. . Cell 180:(4):764–79.e20
     [Crossref] [Google Scholar]
  17. 17.
    Rohlenova K, Goveia J, García-Caballero M, Subramanian A, Kalucka J, et al. 2020.. Single-cell RNA sequencing maps endothelial metabolic plasticity in pathological angiogenesis. . Cell Metab. 31:(4):862–77.e14
     [Crossref] [Google Scholar]
  18. 18.
    Sabbagh MF, Heng JS, Luo C, Castanon RG, Nery JR, et al. 2018.. Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells. . eLife 7::e36187
     [Crossref] [Google Scholar]
  19. 19.
    Zhang K, Kan H, Mao A, Yu F, Geng L, et al. 2024.. Integrated single-cell transcriptomic atlas of human kidney endothelial cells. . J. Am. Soc. Nephrol. 35:(5):578–93
     [Crossref] [Google Scholar]
  20. 20.
    Rafii S, Butler JM, Ding B-S. 2016.. Angiocrine functions of organ-specific endothelial cells. . Nature 529:(7586):316–25
     [Crossref] [Google Scholar]
  21. 21.
    Guo P, Poulos MG, Palikuqi B, Badwe CR, Lis R, et al. 2017.. Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression. . J. Clin. Investig. 127:(12):4242–56
     [Crossref] [Google Scholar]
  22. 22.
    Gunawardana H, Romero T, Yao N, Heidt S, Mulder A, et al. 2021.. Tissue-specific endothelial cell heterogeneity contributes to unequal inflammatory responses. . Sci. Rep. 11:(1):1949
     [Crossref] [Google Scholar]
  23. 23.
    Cao Z, Scandura JM, Inghirami GG, Shido K, Ding B-S, Rafii S. 2017.. Molecular checkpoint decisions made by subverted vascular niche transform indolent tumor cells into chemoresistant cancer stem cells. . Cancer Cell 31:(1):110–26
     [Crossref] [Google Scholar]
  24. 24.
    Wieland E, Rodriguez-Vita J, Liebler SS, Mogler C, Moll I, et al. 2017.. Endothelial Notch1 activity facilitates metastasis. . Cancer Cell 31:(3):355–67
     [Crossref] [Google Scholar]
  25. 25.
    Ding B-S, Cao Z, Lis R, Nolan DJ, Guo P, et al. 2014.. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. . Nature 505:(7481):97–102
     [Crossref] [Google Scholar]
  26. 26.
    Gomez-Salinero JM, Rafii S. 2018.. Endothelial cell adaptation in regeneration. . Science 362:(6419):1116–17
     [Crossref] [Google Scholar]
  27. 27.
    Kusumbe AP, Ramasamy SK, Itkin T, Mäe MA, Langen UH, et al. 2016.. Age-dependent modulation of vascular niches for haematopoietic stem cells. . Nature 532:(7599):380–84
     [Crossref] [Google Scholar]
  28. 28.
    Poulos MG, Ramalingam P, Gutkin MC, Llanos P, Gilleran K, et al. 2017.. Endothelial transplantation rejuvenates aged hematopoietic stem cell function. . J. Clin. Investig. 127:(11):4163–78
     [Crossref] [Google Scholar]
  29. 29.
    Lee J-H, Bhang DH, Beede A, Huang TL, Stripp BR, et al. 2014.. Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. . Cell 156:(3):440–55
     [Crossref] [Google Scholar]
  30. 30.
    Rafii S, Cao Z, Lis R, Siempos II, Chavez D, et al. 2015.. Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration. . Nat. Cell Biol. 17:(2):123–36
     [Crossref] [Google Scholar]
  31. 31.
    Ding B-S, Nolan DJ, Guo P, Babazadeh AO, Cao Z, et al. 2011.. Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. . Cell 147:(3):539–53
     [Crossref] [Google Scholar]
  32. 32.
    Dejana E, Hirschi KK, Simons M. 2017.. The molecular basis of endothelial cell plasticity. . Nat. Commun. 8::14361
     [Crossref] [Google Scholar]
  33. 33.
    Gritz E, Hirschi KK. 2016.. Specification and function of hemogenic endothelium during embryogenesis. . Cell. Mol. Life Sci. 73:(8):1547–67
     [Crossref] [Google Scholar]
  34. 34.
    Kovacic JC, Mercader N, Torres M, Boehm M, Fuster V. 2012.. Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease. . Circulation 125:(14):1795–808
     [Crossref] [Google Scholar]
  35. 35.
    Greenspan LJ, Weinstein BM. 2021.. To be or not to be: endothelial cell plasticity in development, repair, and disease. . Angiogenesis 24:(2):251–69
     [Crossref] [Google Scholar]
  36. 36.
    Jambusaria A, Hong Z, Zhang L, Srivastava S, Jana A, et al. 2020.. Endothelial heterogeneity across distinct vascular beds during homeostasis and inflammation. . eLife 9::e51413
     [Crossref] [Google Scholar]
  37. 37.
    Ellis LV, Cain MP, Hutchison V, Flodby P, Crandall ED, et al. 2020.. Epithelial Vegfa specifies a distinct endothelial population in the mouse lung. . Dev. Cell 52:(5):617–30.e6
     [Crossref] [Google Scholar]
  38. 38.
    Niethamer TK, Stabler CT, Leach JP, Zepp JA, Morley MP, et al. 2020.. Defining the role of pulmonary endothelial cell heterogeneity in the response to acute lung injury. . eLife 9::e53072
     [Crossref] [Google Scholar]
  39. 39.
    Gillich A, Zhang F, Farmer CG, Travaglini KJ, Tan SY, et al. 2020.. Capillary cell-type specialization in the alveolus. . Nature 586:(7831):785–89
     [Crossref] [Google Scholar]
  40. 40.
    Hogan BLM, Barkauskas CE, Chapman HA, Epstein JA, Jain R, et al. 2014.. Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. . Cell Stem Cell 15:(2):123–38
     [Crossref] [Google Scholar]
  41. 41.
    Yang J, Hernandez BJ, Martinez Alanis D, Narvaez del Pilar O, Vila-Ellis L, et al. 2016.. The development and plasticity of alveolar type 1 cells. . Development 143:(1):54–65
     [Google Scholar]
  42. 42.
    Sun X, Perl A-K, Li R, Bell SM, Sajti E, et al. 2022.. A census of the lung: CellCards from LungMAP. . Dev. Cell 57:(1):112–45.e2
     [Crossref] [Google Scholar]
  43. 43.
    Basil MC, Cardenas-Diaz FL, Kathiriya JJ, Morley MP, Carl J, et al. 2022.. Human distal airways contain a multipotent secretory cell that can regenerate alveoli. . Nature 604:(7904):120–26
     [Crossref] [Google Scholar]
  44. 44.
    Travaglini KJ, Nabhan AN, Penland L, Sinha R, Gillich A, et al. 2020.. A molecular cell atlas of the human lung from single-cell RNA sequencing. . Nature 587:(7835):619–25
     [Crossref] [Google Scholar]
  45. 45.
    Katz AM. 1957.. Knowledge of the circulation before William Harvey. . Circulation 15::726–34
     [Crossref] [Google Scholar]
  46. 46.
    Schupp JC, Adams TS, Cosme C, Raredon MSB, Yuan Y, et al. 2021.. Integrated single-cell atlas of endothelial cells of the human lung. . Circulation 144:(4):286–302
     [Crossref] [Google Scholar]
  47. 47.
    Schupp JC, Manning EP, Chioccioli M, Kamp JC, Christian L, et al. 2023.. Alveolar vascular remodeling in nonspecific interstitial pneumonia: replacement of normal lung capillaries with COL15A1-positive endothelial cells. . Am. J. Respir. Crit. Care Med. 208:(7):819–22
     [Crossref] [Google Scholar]
  48. 48.
    Adams TS, Schupp JC, Poli S, Ayaub EA, Neumark N, et al. 2020.. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. . Sci. Adv. 6:(28):eaba1983
     [Crossref] [Google Scholar]
  49. 49.
    Schiller HB, Montoro DT, Simon LM, Rawlins EL, Meyer KB, et al. 2019.. The Human Lung Cell Atlas: a high-resolution reference map of the human lung in health and disease. . Am. J. Respir. Cell Mol. Biol. 61:(1):31–41
     [Crossref] [Google Scholar]
  50. 50.
    Sikkema L, Ramírez-Suástegui C, Strobl DC, Gillett TE, Zappia L, et al. 2023.. An integrated cell atlas of the lung in health and disease. . Nat. Med. 29:(6):1563–77
     [Crossref] [Google Scholar]
  51. 51.
    Guo M, Morley MP, Jiang C, Wu Y, Li G, et al. 2023.. Guided construction of single cell reference for human and mouse lung. . Nat. Commun. 14::4566
     [Crossref] [Google Scholar]
  52. 52.
    Du Y, Ouyang W, Kitzmiller JA, Guo M, Zhao S, et al. 2021.. Lung gene expression analysis web portal version 3: lung-at-a-glance. . Am. J. Respir. Cell Mol. Biol. 64:(1):146–49
     [Crossref] [Google Scholar]
  53. 53.
    Adams TS, Marlier A, Kaminski N. 2023.. Lung cell atlases in health and disease. . Annu. Rev. Physiol. 85::47–69
     [Crossref] [Google Scholar]
  54. 54.
    Zepp JA, Morley MP, Loebel C, Kremp MM, Chaudhry FN, et al. 2021.. Genomic, epigenomic, and biophysical cues controlling the emergence of the lung alveolus. . Science 371:(6534):eabc3172
     [Crossref] [Google Scholar]
  55. 55.
    Guo M, Du Y, Gokey JJ, Ray S, Bell SM, et al. 2019.. Single cell RNA analysis identifies cellular heterogeneity and adaptive responses of the lung at birth. . Nat. Commun. 10::37
     [Crossref] [Google Scholar]
  56. 56.
    Duong TE, Wu Y, Sos BC, Dong W, Limaye S, et al. 2022.. A single-cell regulatory map of postnatal lung alveologenesis in humans and mice. . Cell Genom. 2:(3):100108
     [Crossref] [Google Scholar]
  57. 57.
    Negretti NM, Plosa EJ, Benjamin JT, Schuler BA, Habermann AC, et al. 2021.. A single-cell atlas of mouse lung development. . Development 148:(24):dev199512
     [Crossref] [Google Scholar]
  58. 58.
    Zanini F, Che X, Knutsen C, Liu M, Suresh NE, et al. 2023.. Developmental diversity and unique sensitivity to injury of lung endothelial subtypes during postnatal growth. . iScience 26:(3):106097
     [Crossref] [Google Scholar]
  59. 59.
    Chandrasekaran P, Negretti NM, Sivakumar A, Liberti DC, Wen H, et al. 2022.. CXCL12 defines lung endothelial heterogeneity and promotes distal vascular growth. . Development 149:(21):dev200909
     [Crossref] [Google Scholar]
  60. 60.
    He P, Lim K, Sun D, Pett JP, Jeng Q, et al. 2022.. A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates. . Cell 185:(25):4841–60.e25
     [Crossref] [Google Scholar]
  61. 61.
    Lim K, Donovan APA, Tang W, Sun D, He P, et al. 2023.. Organoid modeling of human fetal lung alveolar development reveals mechanisms of cell fate patterning and neonatal respiratory disease. . Cell Stem Cell 30:(1):20–37.e9
     [Crossref] [Google Scholar]
  62. 62.
    Liu Q, Huang X, Zhang H, Tian X, He L, et al. 2015.. c-kit+ cells adopt vascular endothelial but not epithelial cell fates during lung maintenance and repair. . Nat. Med. 21:(8):866–68
     [Crossref] [Google Scholar]
  63. 63.
    Ren X, Ustiyan V, Guo M, Wang G, Bolte C, et al. 2019.. Postnatal alveologenesis depends on FOXF1 signaling in c-KIT+ endothelial progenitor cells. . Am. J. Respir. Crit. Care Med. 200:(9):1164–76
     [Crossref] [Google Scholar]
  64. 64.
    Wang G, Wen B, Ren X, Li E, Zhang Y, et al. 2021.. Generation of pulmonary endothelial progenitor cells for cell-based therapy using interspecies mouse-rat chimeras. . Am. J. Respir. Crit. Care Med. 204:(3):326–38
     [Crossref] [Google Scholar]
  65. 65.
    Toth A, Steinmeyer S, Kannan P, Gray J, Jackson CM, et al. 2022.. Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates. . Sci. Transl. Med. 14:(638):eabl8574
     [Crossref] [Google Scholar]
  66. 66.
    Guo M, Wikenheiser-Brokamp KA, Kitzmiller JA, Jiang C, Wang G, et al. 2023.. Single cell multiomics identifies cells and genetic networks underlying alveolar capillary dysplasia. . Am. J. Respir. Crit. Care Med. 208:(6):709–25
     [Crossref] [Google Scholar]
  67. 67.
    Ellis LV, Bywaters JD, Chen J. 2024.. Endothelial deletion of p53 generates transitional endothelial cells and improves lung development during neonatal hyperoxia. . bioRxiv 593014. https://doi.org/10.1101/2024.05.07.593014
  68. 68.
    Xia S, Ellis LV, Winkley K, Menden H, Mabry SM, et al. 2023.. Neonatal hyperoxia induces activated pulmonary cellular states and sex-dependent transcriptomic changes in a model of experimental bronchopulmonary dysplasia. . Am. J. Physiol. Lung Cell. Mol. Physiol. 324:(2):L123–40
     [Crossref] [Google Scholar]
  69. 69.
    Cantu A, Gutierrez MC, Dong X, Leek C, Sajti E, Lingappan K. 2023.. Remarkable sex-specific differences at single-cell resolution in neonatal hyperoxic lung injury. . Am. J. Physiol. Lung Cell. Mol. Physiol. 324:(1):L5–31
     [Crossref] [Google Scholar]
  70. 70.
    Long Y, Chen H, Ning J. 2022.. Deficiency of endothelial FGFR1 alleviates hyperoxia-induced bronchopulmonary dysplasia in neonatal mice. . Front. Pharmacol. 13::1039103
     [Crossref] [Google Scholar]
  71. 71.
    Lingappan K, Jiang W, Wang L, Moorthy B. 2016.. Sex-specific differences in neonatal hyperoxic lung injury. . Am. J. Physiol. Lung Cell. Mol. Physiol. 311:(2):L481–93
     [Crossref] [Google Scholar]
  72. 72.
    Coarfa C, Zhang Y, Maity S, Perera DN, Jiang W, et al. 2017.. Sexual dimorphism of the pulmonary transcriptome in neonatal hyperoxic lung injury: identification of angiogenesis as a key pathway. . Am. J. Physiol. Lung Cell. Mol. Physiol. 313:(6):L991–1005
     [Crossref] [Google Scholar]
  73. 73.
    Cantu A, Cantu Gutierrez M, Zhang Y, Dong X, Lingappan K. 2023.. Endothelial to mesenchymal transition in neonatal hyperoxic lung injury: role of sex as a biological variable. . Physiol. Genom. 55:(8):345–54
     [Crossref] [Google Scholar]
  74. 74.
    Zhao G, Weiner AI, Neupauer KM, de Mello Costa MF, Palashikar G, et al. 2020.. Regeneration of the pulmonary vascular endothelium after viral pneumonia requires COUP-TF2. . Sci. Adv. 6:(48):eabc4493
     [Crossref] [Google Scholar]
  75. 75.
    Zhang L, Gao S, White Z, Dai Y, Malik AB, Rehman J. 2022.. Single-cell transcriptomic profiling of lung endothelial cells identifies dynamic inflammatory and regenerative subpopulations. . JCI Insight 7:(11):e158079
     [Crossref] [Google Scholar]
  76. 76.
    Niethamer TK, Levin LI, Morley MP, Babu A, Zhou S, Morrisey EE. 2023.. Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration. . eLife 12::e83835
     [Crossref] [Google Scholar]
  77. 77.
    Zhao G, Xue L, Weiner AI, Gong N, Adams-Tzivelekidis S, et al. 2024.. TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue. . Sci. Transl. Med. 16:(732):eadg6229
     [Crossref] [Google Scholar]
  78. 78.
    Zhao G, Gentile ME, Xue L, Cosgriff CV, Weiner AI, et al. 2024.. Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation. . Nat. Commun. 15::4235
     [Crossref] [Google Scholar]
  79. 79.
    Niethamer TK, Planer JD, Morley MP, Babu A, Basil MC, et al. 2024.. A longitudinal atlas of post-viral lung regeneration reveals persistent injury-associated cell states. . bioRxiv 595801. https://doi.org/10.1101/2024.05.24.595801
  80. 80.
    Kasmani MY, Topchyan P, Brown AK, Brown RJ, Wu X, et al. 2023.. A spatial sequencing atlas of age-induced changes in the lung during influenza infection. . Nat. Commun. 14::6597
     [Crossref] [Google Scholar]
  81. 81.
    Lui KO, Ma Z, Dimmeler S. 2024.. SARS-CoV-2 induced vascular endothelial dysfunction: Direct or indirect effects?. Cardiovasc. Res. 120:(1):34–43
     [Crossref] [Google Scholar]
  82. 82.
    Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, et al. 2020.. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. . N. Engl. J. Med. 383:(2):120–28
     [Crossref] [Google Scholar]
  83. 83.
    Rendeiro AF, Ravichandran H, Bram Y, Chandar V, Kim J, et al. 2021.. The spatial landscape of lung pathology during COVID-19 progression. . Nature 593:(7860):564–69
     [Crossref] [Google Scholar]
  84. 84.
    Milross L, Hunter B, McDonald D, Merces G, Thomson A, et al. 2024.. Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19. . eBioMedicine 99::104945
     [Crossref] [Google Scholar]
  85. 85.
    Delorey TM, Ziegler CGK, Heimberg G, Normand R, Yang Y, et al. 2021.. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. . Nature 595:(7865):107–13
     [Crossref] [Google Scholar]
  86. 86.
    COVID Tissue Atlas Consort., Granados AA, Bucher S, Song H, Agrawal A, et al. 2023.. Single-nuclei characterization of pervasive transcriptional signatures across organs in response to COVID-19. . eLife 12::e81090
     [Crossref] [Google Scholar]
  87. 87.
    de Rooij LPMH, Becker LM, Teuwen L-A, Boeckx B, Jansen S, et al. 2023.. The pulmonary vasculature in lethal COVID-19 and idiopathic pulmonary fibrosis at single-cell resolution. . Cardiovasc. Res. 119:(2):520–35
     [Crossref] [Google Scholar]
  88. 88.
    Passi R, Cholewa-Waclaw J, Wereski R, Bennett M, Veizades S, et al. 2024.. COVID-19 plasma induces subcellular remodelling within the pulmonary microvascular endothelium. . Vasc. Pharmacol. 154::107277
     [Crossref] [Google Scholar]
  89. 89.
    Alon R, Sportiello M, Kozlovski S, Kumar A, Reilly EC, et al. 2021.. Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19. . Nat. Rev. Immunol. 21::49–64
     [Crossref] [Google Scholar]
  90. 90.
    Xie T, Wang Y, Deng N, Huang G, Taghavifar F, et al. 2018.. Single-cell deconvolution of fibroblast heterogeneity in mouse pulmonary fibrosis. . Cell Rep. 22:(13):3625–40
     [Crossref] [Google Scholar]
  91. 91.
    Li R, Bernau K, Sandbo N, Gu J, Preissl S, Sun X. 2018.. Pdgfra marks a cellular lineage with distinct contributions to myofibroblasts in lung maturation and injury response. . eLife 7::e36865
     [Crossref] [Google Scholar]
  92. 92.
    Tsukui T, Sun K-H, Wetter JB, Wilson-Kanamori JR, Hazelwood LA, et al. 2020.. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. . Nat. Commun. 11::1920
     [Crossref] [Google Scholar]
  93. 93.
    Ushakumary MG, Riccetti M, Perl A-KT. 2021.. Resident interstitial lung fibroblasts and their role in alveolar stem cell niche development, homeostasis, injury, and regeneration. . Stem Cells Transl. Med. 10:(7):1021–32
     [Crossref] [Google Scholar]
  94. 94.
    Barkauskas CE, Noble PW. 2014.. Cellular mechanisms of tissue fibrosis. 7. New insights into the cellular mechanisms of pulmonary fibrosis. . Am. J. Physiol. Cell Physiol. 306:(11):C987–996
     [Crossref] [Google Scholar]
  95. 95.
    Katzen J, Beers MF. 2020.. Contributions of alveolar epithelial cell quality control to pulmonary fibrosis. . J. Clin. Investig. 130:(10):5088–99
     [Crossref] [Google Scholar]
  96. 96.
    Xu Y, Mizuno T, Sridharan A, Du Y, Guo M, et al. 2016.. Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. . JCI Insight 1:(20):e90558
     [Crossref] [Google Scholar]
  97. 97.
    Strunz M, Simon LM, Ansari M, Kathiriya JJ, Angelidis I, et al. 2020.. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. . Nat. Commun. 11::3559
     [Crossref] [Google Scholar]
  98. 98.
    Wang F, Ting C, Riemondy KA, Douglas M, Foster K, et al. 2023.. Regulation of epithelial transitional states in murine and human pulmonary fibrosis. . J. Clin. Investig. 133:(22):e165612
     [Crossref] [Google Scholar]
  99. 99.
    Aran D, Looney AP, Liu L, Wu E, Fong V, et al. 2019.. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. . Nat. Immunol. 20:(2):163–72
     [Crossref] [Google Scholar]
  100. 100.
    Peyser R, MacDonnell S, Gao Y, Cheng L, Kim Y, et al. 2019.. Defining the activated fibroblast population in lung fibrosis using single-cell sequencing. . Am. J. Respir. Cell Mol. Biol. 61:(1):74–85
     [Crossref] [Google Scholar]
  101. 101.
    Trogisch FA, Abouissa A, Keles M, Birke A, Fuhrmann M, et al. 2024.. Endothelial cells drive organ fibrosis in mice by inducing expression of the transcription factor SOX9. . Sci. Transl. Med. 16:(736):eabq4581
     [Crossref] [Google Scholar]
  102. 102.
    Knipe RS, Spinney JJ, Abe EA, Probst CK, Franklin A, et al. 2022.. Endothelial-specific loss of sphingosine-1-phosphate receptor 1 increases vascular permeability and exacerbates bleomycin-induced pulmonary fibrosis. . Am. J. Respir. Cell Mol. Biol. 66:(1):38–52
     [Crossref] [Google Scholar]
  103. 103.
    Brazee PL, Cartier A, Kuo A, Haring AM, Nguyen T, et al. 2024.. Augmentation of endothelial S1PR1 attenuates postviral pulmonary fibrosis. . Am. J. Respir. Cell Mol. Biol. 70:(2):119–28
     [Crossref] [Google Scholar]
  104. 104.
    Liu X, Qin X, Qin H, Jia C, Yuan Y, et al. 2021.. Characterization of the heterogeneity of endothelial cells in bleomycin-induced lung fibrosis using single-cell RNA sequencing. . Angiogenesis 24:(4):809–21
     [Crossref] [Google Scholar]
  105. 105.
    Raslan AA, Pham TX, Lee J, Kontodimas K, Tilston-Lunel A, et al. 2024.. Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis. . Nat. Commun. 15::5449
     [Crossref] [Google Scholar]
  106. 106.
    Degryse AL, Tanjore H, Xu XC, Polosukhin VV, Jones BR, et al. 2010.. Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis. . Am. J. Physiol. Lung Cell. Mol. Physiol. 299:(4):L442–52
     [Crossref] [Google Scholar]
  107. 107.
    Habermann AC, Gutierrez AJ, Bui LT, Yahn SL, Winters NI, et al. 2020.. Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis. . Sci. Adv. 6:(28):eaba1972
     [Crossref] [Google Scholar]
  108. 108.
    Carraro G, Mulay A, Yao C, Mizuno T, Konda B, et al. 2020.. Single-cell reconstruction of human basal cell diversity in normal and idiopathic pulmonary fibrosis lungs. . Am. J. Respir. Crit. Care Med. 202:(11):1540–50
     [Crossref] [Google Scholar]
  109. 109.
    Reyfman PA, Walter JM, Joshi N, Anekalla KR, McQuattie-Pimentel AC, et al. 2019.. Single-cell transcriptomic analysis of human lung provides insights into the pathobiology of pulmonary fibrosis. . Am. J. Respir. Crit. Care Med. 199:(12):1517–36
     [Crossref] [Google Scholar]
  110. 110.
    Neumark N, Cosme C, Rose K-A, Kaminski N. 2020.. The Idiopathic Pulmonary Fibrosis Cell Atlas. . Am. J. Physiol. Lung Cell. Mol. Physiol. 319:(6):L887–92
     [Crossref] [Google Scholar]
  111. 111.
    Mayr CH, Simon LM, Leuschner G, Ansari M, Schniering J, et al. 2021.. Integrative analysis of cell state changes in lung fibrosis with peripheral protein biomarkers. . EMBO Mol. Med. 13:(4):e12871
     [Crossref] [Google Scholar]
  112. 112.
    Kathiriya JJ, Wang C, Zhou M, Brumwell A, Cassandras M, et al. 2022.. Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells. . Nat. Cell Biol. 24::10–23
     [Crossref] [Google Scholar]
  113. 113.
    Morse C, Tabib T, Sembrat J, Buschur KL, Bittar HT, et al. 2019.. Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis. . Eur. Respir. J. 54:(2):1802441
     [Crossref] [Google Scholar]
  114. 114.
    Probst CK, Montesi SB, Medoff BD, Shea BS, Knipe RS. 2020.. Vascular permeability in the fibrotic lung. . Eur. Respir. J. 56:(1):1900100
     [Crossref] [Google Scholar]
  115. 115.
    Lang NJ, Gote-Schniering J, Porras-Gonzalez D, Yang L, De Sadeleer LJ, et al. 2023.. Ex vivo tissue perturbations coupled to single-cell RNA-seq reveal multilineage cell circuit dynamics in human lung fibrogenesis. . Sci. Transl. Med. 15:(725):eadh0908
     [Crossref] [Google Scholar]
  116. 116.
    Humbert M, Guignabert C, Bonnet S, Dorfmüller P, Klinger JR, et al. 2019.. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. . Eur. Respir. J. 53:(1):1801887
     [Crossref] [Google Scholar]
  117. 117.
    Singh N, Eickhoff C, Garcia-Agundez A, Bertone P, Paudel SS, et al. 2023.. Transcriptional profiles of pulmonary artery endothelial cells in pulmonary hypertension. . Sci. Rep. 13::22534
     [Crossref] [Google Scholar]
  118. 118.
    Crnkovic S, Valzano F, Fließer E, Gindlhuber J, Thekkekara Puthenparampil H, et al. 2022.. Single-cell transcriptomics reveals skewed cellular communication and phenotypic shift in pulmonary artery remodeling. . JCI Insight 7:(20):e153471
     [Crossref] [Google Scholar]
  119. 119.
    Saygin D, Tabib T, Bittar HET, Valenzi E, Sembrat J, et al. 2020.. Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension. . Pulm. Circ. 10:(1):1–15
     [Crossref] [Google Scholar]
  120. 120.
    Stearman RS, Bui QM, Speyer G, Handen A, Cornelius AR, et al. 2019.. Systems analysis of the human pulmonary arterial hypertension lung transcriptome. . Am. J. Respir. Cell Mol. Biol. 60:(6):637–49
     [Crossref] [Google Scholar]
  121. 121.
    Asosingh K, Comhair S, Mavrakis L, Xu W, Horton D, et al. 2021.. Single-cell transcriptomic profile of human pulmonary artery endothelial cells in health and pulmonary arterial hypertension. . Sci. Rep. 11::14714
     [Crossref] [Google Scholar]
  122. 122.
    Lin SM, Rue R, Mukhitov AR, Goel A, Basil MC, et al. 2023.. Hyperactive mTORC1 in lung mesenchyme induces endothelial cell dysfunction and pulmonary vascular remodeling. . J. Clin. Investig. 134:(4):e172116
     [Crossref] [Google Scholar]
  123. 123.
    Zhang J, Xu C, Tang X, Sun S, Liu S, et al. 2024.. Endothelium-specific SIRT7 targeting ameliorates pulmonary hypertension through Krüpple-like factor 4 deacetylation. . Cardiovasc. Res. 120:(4):403–16
     [Crossref] [Google Scholar]
  124. 124.
    Piper B, Bogamuwa S, Hossain T, Farkas D, Rosas L, et al. 2024.. RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension. . J. Clin. Investig. 134:(3):e169441
     [Crossref] [Google Scholar]
  125. 125.
    Theodorakopoulou MP, Alexandrou ME, Bakaloudi DR, Pitsiou G, Stanopoulos I, et al. 2021.. Endothelial dysfunction in COPD: a systematic review and meta-analysis of studies using different functional assessment methods. . ERJ Open Res. 7:(2):00983-2020
     [Crossref] [Google Scholar]
  126. 126.
    Clarenbach CF, Senn O, Sievi NA, Camen G, van Gestel AJR, et al. 2013.. Determinants of endothelial function in patients with COPD. . Eur. Respir. J. 42:(5):1194–204
     [Crossref] [Google Scholar]
  127. 127.
    Polverino F, Celli BR, Owen CA. 2018.. COPD as an endothelial disorder: Endothelial injury linking lesions in the lungs and other organs? (2017 Grover Conference Series). . Pulm. Circ. 8:(1):1–18
     [Crossref] [Google Scholar]
  128. 128.
    Hisata S, Racanelli AC, Kermani P, Schreiner R, Houghton S, et al. 2021.. Reversal of emphysema by restoration of pulmonary endothelial cells. . J. Exp. Med. 218:(8):e20200938
     [Crossref] [Google Scholar]
  129. 129.
    Wang Z, Yan N, Sheng H, Xiao Y, Sun J, Cao C. 2024.. Single-cell transcriptomic analysis reveals an immunosuppressive network between POSTN CAFs and ACKR1 ECs in TKI-resistant lung cancer. . Cancer Genom. Proteom. 21:(1):65–78
     [Crossref] [Google Scholar]
  130. 130.
    Armani G, Pozzi E, Pagani A, Porta C, Rizzo M, et al. 2021.. The heterogeneity of cancer endothelium: the relevance of angiogenesis and endothelial progenitor cells in cancer microenvironment. . Microvasc. Res. 138::104189
     [Crossref] [Google Scholar]
  131. 131.
    Jakab M, Lee KH, Uvarovskii A, Ovchinnikova S, Kulkarni SR, et al. 2024.. Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency. . Nat. Cancer 5::716–30
     [Crossref] [Google Scholar]
  132. 132.
    Goveia J, Rohlenova K, Taverna F, Treps L, Conradi L-C, et al. 2020.. An integrated gene expression landscape profiling approach to identify lung tumor endothelial cell heterogeneity and angiogenic candidates. . Cancer Cell 37:(1):21–36.e13
     [Crossref] [Google Scholar]
  133. 133.
    Ribatti D, Annese T, Tamma R. 2023.. Vascular co-option in resistance to anti-angiogenic therapy. . Front. Oncol. 13::1323350
     [Crossref] [Google Scholar]
  134. 134.
    Bian F, Goda C, Wang G, Lan Y-W, Deng Z, et al. 2024.. FOXF1 promotes tumor vessel normalization and prevents lung cancer progression through FZD4. . EMBO Mol. Med. 16:(5):1063–90
     [Crossref] [Google Scholar]
  135. 135.
    Qiao Q, Liu X, Yang T, Cui K, Kong L, et al. 2021.. Nanomedicine for acute respiratory distress syndrome: the latest application, targeting strategy, and rational design. . Acta Pharm. Sin. B 11:(10):3060–91
     [Crossref] [Google Scholar]
  136. 136.
    Mi P. 2020.. Stimuli-responsive nanocarriers for drug delivery, tumor imaging, therapy and theranostics. . Theranostics 10:(10):4557–88
     [Crossref] [Google Scholar]
  137. 137.
    Deng Z, Kalin GT, Shi D, Kalinichenko VV. 2021.. Nanoparticle delivery systems with cell-specific targeting for pulmonary diseases. . Am. J. Respir. Cell Mol. Biol. 64:(3):292–307
     [Crossref] [Google Scholar]
  138. 138.
    Gentile F, Curcio A, Indolfi C, Ferrari M, Decuzzi P. 2008.. The margination propensity of spherical particles for vascular targeting in the microcirculation. . J. Nanobiotechnol. 6:(1):9
     [Crossref] [Google Scholar]
  139. 139.
    Brenner JS, Pan DC, Myerson JW, Marcos-Contreras OA, Villa CH, et al. 2018.. Red blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude. . Nat. Commun. 9::2684
     [Crossref] [Google Scholar]
  140. 140.
    Zhao G, Xue L, Geisler HC, Xu J, Li X, et al. 2024.. Precision treatment of viral pneumonia through macrophage-targeted lipid nanoparticle delivery. . PNAS 121:(7):e2314747121
     [Crossref] [Google Scholar]
  141. 141.
    Ferguson LT, Hood ED, Shuvaeva T, Shuvaev VV, Basil MC, et al. 2022.. Dual affinity to RBCs and target cells (DART) enhances both organ- and cell type-targeting of intravascular nanocarriers. . ACS Nano 16:(3):4666–83
     [Crossref] [Google Scholar]
  142. 142.
    Sun F, Wang G, Pradhan A, Xu K, Gomez-Arroyo J, et al. 2021.. Nanoparticle delivery of STAT3 alleviates pulmonary hypertension in a mouse model of alveolar capillary dysplasia. . Circulation 144:(7):539–55
     [Crossref] [Google Scholar]
  143. 143.
    Wang G, Wen B, Deng Z, Zhang Y, Kolesnichenko OA, et al. 2022.. Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling. . Nat. Commun. 13::2080
     [Crossref] [Google Scholar]
  144. 144.
    Kohram F, Deng Z, Zhang Y, Al Reza A, Li E, et al. 2023.. Demonstration of safety in wild type mice of npFOXF1, a novel nanoparticle-based gene therapy for alveolar capillary dysplasia with misaligned pulmonary veins. . Biol. Targets Ther. 17::43–55
     [Crossref] [Google Scholar]
  145. 145.
    Nguyen J, Lin Y-Y, Gerecht S. 2021.. The next generation of endothelial differentiation: tissue-specific ECs. . Cell Stem Cell 28:(7):1188–204
     [Crossref] [Google Scholar]
  146. 146.
    Miao Y, Tan C, Pek NM, Yu Z, Iwasawa K, et al. 2024.. Deciphering endothelial and mesenchymal organ specification in vascularized lung and intestinal organoids. . bioRxiv 577460. https://doi.org/10.1101/2024.02.06.577460
  147. 147.
    Herriges MJ, Yampolskaya M, Thapa BR, Lindstrom-Vautrin J, Wang F, et al. 2023.. Durable alveolar engraftment of PSC-derived lung epithelial cells into immunocompetent mice. . Cell Stem Cell 30:(9):1217–34.e7
     [Crossref] [Google Scholar]
  148. 148.
    Ma L, Thapa BR, Le Suer JA, Tilston-Lünel A, Herriges MJ, et al. 2023.. Airway stem cell reconstitution by the transplantation of primary or pluripotent stem cell-derived basal cells. . Cell Stem Cell 30:(9):1199–1216.e7
     [Crossref] [Google Scholar]
  149. 149.
    Ikonomou L, Wagner DE, Turner L, Weiss DJ. 2019.. Translating basic research into safe and effective cell-based treatments for respiratory diseases. . Ann. Am. Thorac. Soc. 16:(6):657–68
     [Crossref] [Google Scholar]
  150. 150.
    Granton J, Langleben D, Kutryk MB, Camack N, Galipeau J, et al. 2015.. Endothelial NO-synthase gene-enhanced progenitor cell therapy for pulmonary arterial hypertension: the PHACeT Trial. . Circ. Res. 117:(7):645–54
     [Crossref] [Google Scholar]
  151. 151.
    Kolesnichenko OA, Flood HM, Zhang Y, Ustiyan V, Cuervo Jimenez HK, et al. 2023.. Endothelial progenitor cells derived from embryonic stem cells prevent alveolar simplification in a murine model of bronchopulmonary dysplasia. . Front. Cell Dev. Biol. 11::1209518
     [Crossref] [Google Scholar]
  152. 152.
    Williams IM, Wu JC. 2019.. Generation of endothelial cells from human pluripotent stem cells. . Arterioscler. Thromb. Vasc. Biol. 39:(7):1317–29
     [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-physiol-022724-105226
Loading
Specialized Pulmonary Vascular Cells in Development and Disease
Annual Review of Physiology 87, 229 (2025); https://doi.org/10.1146/annurev-physiol-022724-105226
/content/journals/10.1146/annurev-physiol-022724-105226
/content/journals/10.1146/annurev-physiol-022724-105226
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error