Register      Login

VOLUME 1 , ISSUE 1 ( January-March, 2022 ) > List of Articles


Role of the Endothelium in Neonatal Diseases

Olachi J Mezu-Ndubuisi

Keywords : Angiogenesis, Bronchopulmonary dysplasia, Endothelium, Necrotizing enterocolitis, Neonate, Retinopathy of prematurity

Citation Information : Mezu-Ndubuisi OJ. Role of the Endothelium in Neonatal Diseases. 2022; 1 (1):44-57.

DOI: 10.5005/jp-journals-11002-0025

License: CC BY-NC 4.0

Published Online: 31-03-2022

Copyright Statement:  Copyright © 2022; The Author(s).


In both fetal and neonatal physiologic and pathologic processes in most organs, endothelial cells are known to play critical roles. Although the endothelium is one of the most ubiquitous cell type in the body, the tight adherence to the blood vessel wall has made it difficult to study their diverse function and structure. In this article, we have reviewed endothelial cell origins and explored their heterogeneity in terms of structure, function, developmental changes, and their role in inflammatory and infectious diseases. We have also attempted to evaluate the untapped therapeutic potentials of endothelial cells in neonatal disease. This article comprises various peer-reviewed studies, including ours, and an extensive database literature search from EMBASE, PubMed, and Scopus.

  1. Chopra H, Hung MK, Kwong DL, et al. Insights into endothelial progenitor cells: origin, classification, potentials, and prospects. Stem Cells Int 2018:9847015. DOI: 10.1155/2018/9847015.
  2. Risau W, Flamme I. Vasculogenesis. Annu Rev Cell Dev Biol 1995;11: 73–91. DOI: 10.1146/annurev.cb.11.110195.000445.
  3. Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res 2000;55:15–35. PMID: 11036931.
  4. Zovein AC, Hofmann JJ, Lynch M, et al. Fate tracing reveals the endothelial origin of hematopoietic stem cells. Cell Stem Cell 2008;3(6):625–636. DOI: 10.1016/j.stem.2008.09.018.
  5. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell 2011;146(6):873–887. DOI: 10.1016/j.cell.2011.08.039.
  6. Drake CJ, Fleming PA. Vasculogenesis in the day 6.5 to 9.5 mouse embryo. Blood 2000;95(5):1671–1679. PMID: 10688823.
  7. Dejana E, Hirschi KK, Simons M. The molecular basis of endothelial cell plasticity. Nat Commun 2017;8(1):1–11. DOI: 10.1038/ncomms14361.
  8. Marcelo KL, Goldie LC, Hirschi KK. Regulation of endothelial cell differentiation and specification. Circulation Res 2013;112(9): 1272–1287. DOI: 10.1161/CIRCRESAHA.113.300506.
  9. Lu X, Gong J, Dennery PA, et al. Endothelial-to-mesenchymal transition: Pathogenesis and therapeutic targets for chronic pulmonary and vascular diseases. Biochem Pharmacol 2019;168: 100–107. DOI: 10.1016/j.bcp.2019.06.021.
  10. Chen PY, Schwartz MA, Simons M. Endothelial-to-mesenchymal transition, vascular inflammation, and atherosclerosis. Front Cardiovasc Med 2020;7:53. DOI: 10.3389/fcvm.2020.00053.
  11. Schwartz MA, Vestweber D, Simons M. A unifying concept in vascular health and disease. Science 2018;360(6386):270–271. DOI: 10.1126/science.aat3470.
  12. Plein A, Fantin A, Denti L, et al. Erythro-myeloid progenitors contribute endothelial cells to blood vessels. Nature 2018;562(7726):223–228. DOI: 10.1038/s41586-018-0552-x.
  13. Feng T, Gao Z, Kou S, et al. No evidence for erythro-myeloid progenitor-derived vascular endothelial cells in multiple organs. Circ Res 2020;127(10):1221–1232. DOI: 10.1161/CIRCRESAHA.120.317442.
  14. Murray PDF. The development in vitro of the blood of the early chick embryo. Proc R Soc London Ser B 1932;111(773):497–521. DOI: 10.1098/rspb.1932.0070.
  15. Sabin FR. Studies on the origin of blood-vessels and of red blood-corpuscles as seen in the living blastoderm of chicks during the second day of incubation. In: Contributions to embryology. vol. 9. Carneg Inst.; 1920. p. 214–262.
  16. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981;292(5819):154–156. DOI: 10.1038/292154a0.
  17. Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci 1981;78(12):7634–7638. DOI: 10.1073/pnas.78.12.7634.
  18. Kaufman DS, Hanson ET, Lewis RL, et al. Hematopoietic colony-forming cells derived from human embryonic stem cells. Proc Natl Acad Sci 2001;98(19):10716–10721. DOI: 10.1073/pnas.191362598.
  19. Fraser ST, Ogawaa M, Yu RT, et al. Definitive hematopoietic commitment within the embryonic vascular endothelial-cadherin+ population. Exp Hematol 2002;30(9):1070–1078. DOI: 10.1016/S0301-472X(02)00887-1.
  20. Boisset JC, van Cappellen W, Andrieu-Soler C, et al. In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 2010;464(7285):116–120. DOI: 10.1038/nature08764.
  21. Kissa, K, Herbomel P. Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature 2010;464(7285):112–115. DOI: 10.1038/nature08761.
  22. Lange L, Morgan M, Schambach A. The hemogenic endothelium: a critical source for the generation of PSC-derived hematopoietic stem and progenitor cells. Cell Mol Life Sci 2021;78(9):4143–4160. DOI: 10.1007/s00018-021-03777-y.
  23. Nadin BM, Goodell MA, Hirschi KK. Phenotype and hematopoietic potential of side population cells throughout embryonic development. Blood 2003;102(7):2436–2443. DOI: 10.1182/blood-2003-01-0118.
  24. Eilken HM, Nishikawa SI, Schroeder T. Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature 2009;457(7231):896–900. DOI: 10.1038/nature07760.
  25. Ivanovs A, Rybtsov S, Anderson RA, et al. Identification of the niche and phenotype of the first human hematopoietic stem cells. Stem Cell Rep 2014;2(4):449–456. DOI: 10.1016/j.stemcr.2014.02.004.
  26. Appelbaum FR. Hematopoietic-cell transplantation at 50. New Engl J Med 2007;357(15):1472. DOI: 10.1056/NEJMp078166.
  27. Krause DS, Fackler MJ, Civin CI, et al. CD34: structure, biology, and clinical utility. Blood 1996;87(1):1–13. PMID: 8547630.
  28. Kansas GS. Selectins and their ligands: current concepts and controversies. Blood 1996;88(9):3259–3287. PMID: 8896391.
  29. Qureshi MH, Cook-Mills J, Doherty DE, et al. TNF-α-dependent ICAM-1-and VCAM-1-mediated inflammatory responses are delayed in neonatal mice infected with Pneumocystis carinii. J Immunol 2003;171(9):4700–4707. DOI: 10.4049/jimmunol.171.9.4700.
  30. Malek AM, Izumo S. Mechanism of endothelial cell shape change and cytoskeletal remodeling in response to fluid shear stress. J Cell Sci 1996;109(4):713–726. DOI: 10.1242/jcs.109.4.713.
  31. Reinhart W. Shear-dependence of endothelial functions. Experientia 1994;50(2):87–93. DOI: 10.1007/BF01984940.
  32. Levesque M, Nerem R. The elongation and orientation of cultured endothelial cells in response to shear stress. J Biomech Eng 1985;107(4):341. DOI: 10.1115/1.3138567.
  33. Noria S, Xu F, McCue S, et al. Assembly and reorientation of stress fibers drives morphological changes to endothelial cells exposed to shear stress. Am J Pathol 2004;164(4):1211–1223. DOI: 10.1016/S0002-9440(10)63209-9.
  34. Liu K, Ji K, Guo L, et al. Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia–reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer. Microvascular Res 2014;92:10–18. DOI: 10.1016/j.mvr.2014.01.008.
  35. Aird WC. Endothelial cell heterogeneity. Cold Spring Harbor Perspect Med 2012;2(1):a006429. DOI: 10.1101/cshperspect.a006429.
  36. Wang HU, Chen ZF, Anderson DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 1998;93(5): 741–753. DOI: 10.1016/s0092-8674(00)81436-1.
  37. Lawson ND, Weinstein BM. Arteries and veins: making a difference with zebrafish. Nat Rev Genet 2002;3(9):674–682. DOI: 10.1038/nrg888.
  38. Thurston G, Yancopoulos GD. Gridlock in the blood. Nature 2001;414(6860):163–164. DOI: 10.1038/35102664.
  39. Yamashita JK. Differentiation of arterial, venous, and lymphatic endothelial cells from vascular progenitors. Trends Cardiovasc Med 2007;17(2):59–63. DOI: 10.1016/j.tcm.2007.01.001.
  40. Wigle JT, Harvey N, Detmar M, et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J 2002;21(7):1505–1513. DOI: 10.1093/emboj/21.7.1505.
  41. Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 2004;5(1):74–80. DOI: 10.1038/ni1013.
  42. Cleuren AC, van der Ent MA, Jiang H, et al. The in vivo endothelial cell translatome is highly heterogeneous across vascular beds. Proc Natl Acad Sci 2019;116(47):23618–23624. DOI: 10.1073/pnas.1912409116.
  43. Hirschi KK, Ingram DA, Yoder MC. Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2008;28(9):1584–1595. DOI: 10.1161/ATVBAHA.107.155960.
  44. Pujol BF, Lucibello FC, Gehling UM, et al. Endothelial-like cells derived from human CD14 positive monocytes. Differentiation 2000;65(5):287–300. DOI: 10.1046/j.1432-0436.2000.6550287.x.
  45. Garlanda C, Dejana E. Heterogeneity of endothelial cells: specific markers. Arterioscler Thromb Vasc Biol 1997;17(7):1193–1202. DOI: 10.1161/01.atv.17.7.1193.
  46. Wolburg H, Neuhaus J, Kniesel U, et al. Modulation of tight junction structure in blood-brain barrier endothelial cells. Effects of tissue culture, second messengers and cocultured astrocytes. J Cell Sci 1994;107(5):1347–1357. DOI: 10.1242/jcs.107.5.1347.
  47. Risau W, Wolburg H, Development of the blood-brain barrier. Trends Neurosci 1990;13(5):174–178. DOI: 10.1016/0166-2236(90)90043-a.
  48. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275(5302):964–966. DOI: 10.1126/science.275.5302.964.
  49. Michiels C. Endothelial cell functions. J Cell Physiol 2003;196(3): 430–443. DOI: 10.1002/jcp.10333.
  50. Sosa MAG, Gasperi RD, Rocher AB, et al. Interactions of primary neuroepithelial progenitor and brain endothelial cells: distinct effect on neural progenitor maintenance and differentiation by soluble factors and direct contact. Cell Res 2007;17(7):619–626. DOI: 10.1038/cr.2007.53.
  51. Khan SS, Solomon MA, McCoy JP Jr. Detection of circulating endothelial cells and endothelial progenitor cells by flow cytometry. Cytomet Part B Clin Cytomet J Int Soc Anal Cytol 2005;64(1):1–8. DOI: 10.1002/cyto.b.20040.
  52. Krishnaswamy G, Kelley J, Yerra L, et al. Human endothelium as a source of multifunctional cytokines: molecular regulation and possible role in human disease. J Interferon Cytokine Res 1999;19(2):91–104. DOI: 10.1089/107999099314234.
  53. Bussolino F, Camussi G, Tetta C, et al. Selected cytokines promote the synthesis of platelet-activating factor in vascular endothelial cells: comparison between tumor necrosis factor alpha and beta and interleukin–1. J Lipid Mediat 1990;2:S15–S22. PMID: 2133280.
  54. Collins T, Read MA, Neish AS, et al. Transcriptional regulation of endothelial cell adhesion molecules: NF-κB and cytokine-inducible enhancers. FASEB J 1995;9(10):899–909. PMID: 7542214.
  55. Abdelgawad ME, Desterke C, Uzan G, et al. Single-cell transcriptomic profiling and characterization of endothelial progenitor cells: new approach for finding novel markers. Stem Cell Res Ther 2021;12(1):145. DOI: 10.1186/s13287-021-02185-0.
  56. Sieveking DP, Buckle A, Celermajer DS, et al. Strikingly different angiogenic properties of endothelial progenitor cell subpopulations: insights from a novel human angiogenesis assay. J Am Coll Cardiol 2008;51(6):660–668. DOI: 10.1016/j.jacc.2007.09.059.
  57. Du X, Hu N, Yu H, et al. miR-150 regulates endothelial progenitor cell differentiation via Akt and promotes thrombus resolution. Stem Cell Res Ther 2020;11(1):1–13. DOI: 10.1186/s13287-020-01871-9.
  58. Kalluri AS, Vellarikkal SK, Edelman ER, et al. Single-cell analysis of the normal mouse aorta reveals functionally distinct endothelial cell populations. Circulation 2019;140(2):147–163. DOI: 10.1161/CIRCULATIONAHA.118.038362.
  59. Niethamer TK, Stabler CT, Leach CT, et al. Defining the role of pulmonary endothelial cell heterogeneity in the response to acute lung injury. Elife 2020;9:e53072. DOI: 10.7554/eLife.53072.
  60. Marcu R, Choi YJ, Xue J, et al. Human organ-specific endothelial cell heterogeneity. IScience 2018;4:20–35. DOI: 10.1016/j.isci.2018.05.003.
  61. McCarron JG, Wilson C, Heathcote HR, et al. Heterogeneity and emergent behaviour in the vascular endothelium. Curr Opin Pharmacol 2019;45:23–32. DOI: 10.1016/j.coph.2019.03.008.
  62. Sandoo A, van Zanten JJCSV, Metsios GS, et al. The endothelium and its role in regulating vascular tone. Open Cardiovasc Med J 2010;4:302. DOI: 10.2174/1874192401004010302.
  63. Baldwin AL, Thurston G. Mechanics of endothelial cell architecture and vascular permeability. Crit Rev Biomed Eng 2001;29(2):247. DOI: 10.1615/critrevbiomedeng.v29.i2.20.
  64. Pries AR, Secomb TW, Gaehtgens P. The endothelial surface layer. Pflügers Archiv 2000;440(5):653–666. DOI: 10.1007/s004240000307.
  65. Dejana E, Corada M, Lampugnani MG. Endothelial cell-to-cell junctions. FASEB J 1995;9(10):910–918. PMID: 7615160.
  66. Antonetti DA, Barber AJ, Hollinger LA, et al. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1 A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 1999;274(33):23463–23467. DOI: 10.1074/jbc.274.33.23463.
  67. Suarez S, McCollum GW, Bretz CA, et al. Modulation of VEGF-induced retinal vascular permeability by peroxisome proliferator-activated receptor-β/δ. Invest Ophthalmol Vis Sci 2014;55(12):8232–8240. DOI: 10.1167/iovs.14-14217.
  68. Deissler H, Lang S, Lang GE. VEGF-induced effects on proliferation, migration and tight junctions are restored by ranibizumab (Lucentis) in microvascular retinal endothelial cells. Br J Ophthalmol 2008;92(6):839–843. DOI: 10.1136/bjo.2007.135640.
  69. Bazzoni G, Estrada OMMN, Dejana E. Molecular structure and functional role of vascular tight junctions. Trends Cardiovasc Med 1999;9(6):147–152. DOI: 10.1016/s1050-1738(99)00022-5.
  70. Dejana E. Endothelial adherens junctions: implications in the control of vascular permeability and angiogenesis. J Clin Invest 1996;98(9):1949–1953. DOI: 10.1172/JCI118997.
  71. Dejana E, Orsenigo F, Lampugnani MG. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 2008;121(13):2115–2122. DOI: 10.1242/jcs.017897.
  72. Xiao Z, Zhang Z, Diamond SL. Shear stress induction of the endothelial nitric oxide synthase gene is calcium-dependent but not calcium-activated. J Cell Physiol 1997;171(2):205–211. DOI: 10.1002/(SICI) 1097-4652(199705)171:2<205::AID-JCP11>3.0.CO;2-C.
  73. Folkman J. Tumor angiogenesis: therapeutic implications. New Engl J Med 1971;285(21):1182–1186. DOI: 10.1056/NEJM197111182852108.
  74. Dachs G, Tozer G. Hypoxia modulated gene expression: angiogenesis, metastasis and therapeutic exploitation. Eur J Cancer 2000;36(13):1649–1660. DOI: 10.1016/s0959-8049(00)00159-3.
  75. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9(6):669–676. DOI: 10.1038/nm0603-669.
  76. Yancopoulos GD, Davis S, Gale NW, et al. Vascular-specific growth factors and blood vessel formation. Nature 2000;407(6801):242–248. DOI: 10.1038/35025215.
  77. Vempati P, Popel AS, Mac Gabhann F. Extracellular regulation of VEGF: isoforms, proteolysis, and vascular patterning. Cytokine Growth Factor Rev 2014;25(1):1–19. DOI: 10.1016/j.cytogfr.2013.11.002.
  78. Waltenberger J, Claesson-Welsh L, Siegbahn A, et al. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 1994;269(43):26988–26995. PMID: 7929439.
  79. Gupta K, Kshirsagar S, Li W, et al. VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp Cell Res 1999;247(2):495–504. DOI: 10.1006/excr.1998.4359.
  80. Phng LK, Gerhardt H. Angiogenesis: a team effort coordinated by notch. Dev Cell 2009;16(2):196–208. DOI: 10.1016/j.devcel.2009.01.015.
  81. Jakobsson L, Franco CA, Bentley K, et al. Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat Cell Biol 2010;12(10):943–953. DOI: 10.1038/ncb2103.
  82. Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999;284(5422):1994–1998. DOI: 10.1126/science.284.5422.1994.
  83. Sato TN, Qin Y, Kozak CA, et al. Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc Natl Acad Sci 1993;90(20):9355–9358. DOI: 10.1073/pnas.90.20.9355.
  84. Jones N, Iljin K, Dumont DJ, et al. Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2001;2(4):257–267. DOI: 10.1038/35067005.
  85. Witzenbichler B, Maisonpierre PC, Jones P, et al. Chemotactic properties of angiopoietin-1 and-2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. J Biol Chem 1998;273(29): 18514–18521. DOI: 10.1074/jbc.273.29.18514.
  86. Brkovic A, Pelletier M, Girard D, et al. Angiopoietin chemotactic activities on neutrophils are regulated by PI-3K activation. J Leukocyte Biol 2007;81(4):1093–1101. DOI: 10.1189/jlb.0906580.
  87. Harfouche R, Hasséssian HM, Guo Y, et al. Mechanisms which mediate the antiapoptotic effects of angiopoietin-1 on endothelial cells. Microvasc Res 2002;64(1):135–147. DOI: 10.1006/mvre.2002.2421.
  88. Daly C, Wong V, Burova E, et al. Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes Dev 2004;18(9):1060–1071. DOI: 10.1101/gad.1189704.
  89. Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci 2002;99(17):11205–11210.
  90. Saharinen P, Eklund L, Miettinen J, et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell–cell and cell–matrix contacts. Nat Cell Biol 2008;10(5):527–537. DOI: 10.1038/ncb1715.
  91. Daly C, Pasnikowski E, Burova E, et al. Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells. Proc Natl Acad Sci 2006;103(42):15491–15496. DOI: 10.1073/pnas.0607538103.
  92. Valable S, Bellail A, Lesne S, et al. Angiopoietin-1-induced phosphatidyl-inositol 3-kinase activation prevents neuronal apoptosis. FASEB J 2003;17(3):1–19. DOI: 10.1096/fj.02-0372fje.
  93. Chae JK, Kim I, Lim ST, et al. Coadministration of angiopoietin-1 and vascular endothelial growth factor enhances collateral vascularization. Arterioscler Thromb Vasc Biol 2000;20(12):2573–2578. DOI: 10.1161/01.ATV.20.12.2573.
  94. Bierhaus A, Chen J, Liliensiek B, et al. LPS and cytokine-activated endothelium. Semin Thromb Hemost 2000;26(5):571–587. DOI: 10.1055/s-2000-13214.
  95. Muller WA, Randolph GJ. Migration of leukocytes across endothelium and beyond: molecules involved in the transmigration and fate of monocytes. J Leukocyte Biol 1999;66(5):698–704. DOI: 10.1002/jlb.66.5.698.
  96. Parent C, Eichacker PQ. Neutrophil and endothelial cell interactions in sepsis: the role of adhesion molecules. Infect Dis Clin N Am 1999;13(2):427–447. DOI: 10.1016/s0891-5520(05)70084-2.
  97. Petri B, Bixel MG. Molecular events during leukocyte diapedesis. FEBS J 2006;273(19):4399–4407. DOI: 10.1111/j.1742-4658.2006.05439.x.
  98. Luscinskas FW, Ma S, Nusrat A, et al. Leukocyte transendothelial migration: a junctional affair. Sem Immunol 2002;14(2):105–113. DOI: 10.1006/smim.2001.0347.
  99. Rosen SD. Ligands for L-selectin: homing, inflammation, and beyond. Annu Rev Immunol 2004;22:129–156. DOI: 10.1146/annurev.immunol.21.090501.080131.
  100. Vainer B, Nielsen O. Changed colonic profile of P-selectin, platelet-endothelial cell adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), ICAM-2, and ICAM-3 in inflammatory bowel disease. Clin Exp Immunol 2000;121(2):242–247. DOI: 10.1046/j.1365-2249.2000.01296.x.
  101. Lomakina EB, Waugh RE. Adhesion between human neutrophils and immobilized endothelial ligand vascular cell adhesion molecule 1: divalent ion effects. Biophys J 2009;96(1):276–284. DOI: 10.1016/j.bpj.2008.10.001.
  102. Kirchhofer D, Tschopp TB, Hadváry P, et al. Endothelial cells stimulated with tumor necrosis factor-alpha express varying amounts of tissue factor resulting in inhomogenous fibrin deposition in a native blood flow system. Effects of thrombin inhibitors. J Clin Invest 1994;93(5):2073–2083. DOI: 10.1172/JCI117202.
  103. Schrag SJ, Farley MM, Petit S, et al. Epidemiology of invasive early-onset neonatal sepsis, 2005 to 2014. Pediatrics 2016;138(6):e20162013. DOI: 10.1542/peds.2016-2013.
  104. Greenberg RG, Kandefer S, Do BT, et al. Late-onset sepsis in extremely premature infants: 2000–2011. Pediatr Infect Dis J 2017;36(8):774. DOI: 10.1097/INF.0000000000001570.
  105. Stoll BJ, Hansen NI, Sánchez PJ, et al. Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics 2011;127(5):817–826. DOI: 10.1542/peds.2010-2217.
  106. Karenberg K, Hudalla H, Frommhold D. Leukocyte recruitment in preterm and term infants. Mol Cell Pediatr 2016;3(1):35. DOI: 10.1186/s40348-016-0063-5.
  107. Nussbaum C, Sperandio M. Innate immune cell recruitment in the fetus and neonate. J Reprod Immunol 2011;90(1):74–81. DOI: 10.1016/j.jri.2011.01.022.
  108. Nussbaum C, Gloning A, Pruenster M, et al. Neutrophil and endothelial adhesive function during human fetal ontogeny. J Leukocyte Biol 2013;93(2):175–184. DOI: 10.1189/jlb.0912468.
  109. Zonneveld R, Jongman R, Juliana A, et al. Low serum angiopoietin-1, high serum angiopoietin-2, and high Ang-2/Ang-1 protein ratio are associated with early onset sepsis in surinamese newborns. Shock (Augusta, Ga.) 2017;48(6):638. DOI: 10.1097/SHK.0000000000000903.
  110. Wu KW, Mo JL, Kou ZW, et al. Neurovascular interaction promotes the morphological and functional maturation of cortical neurons. Front Cell Neurosci 2017;11:290. DOI: 10.3389/fncel.2017.00290.
  111. Beaino G, Khoshnood B, Kaminski M, et al. Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population-based cohort study. Dev Med Child Neurol 2010;52(6):e119–e125. DOI: 10.1111/j.1469-8749.2010.03612.x.
  112. Papile LA, Burstein J, Burstein R, et al. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978;92(4):529–534. DOI: 10.1016/s0022-3476(78)80282-0.
  113. Heep A, Behrendt D, Nitsch P, et al. Increased serum levels of interleukin 6 are associated with severe intraventricular haemorrhage in extremely premature infants. Arch Dis Childhood-Fetal Neonatal Ed 2003;88(6):F501–F504. DOI: 10.1136/fn.88.6.f501.
  114. Leviton A, Allred EN, Dammann O, et al. Systemic inflammation, intraventricular hemorrhage, and white matter injury. J Child Neurol 2013;28(12):1637–1645. DOI: 10.1177/0883073812463068.
  115. Borjini N, Sivilia S, Giuliani A, et al. Potential biomarkers for neuroinflammation and neurodegeneration at short and long term after neonatal hypoxic-ischemic insult in rat. J Neuroinflamm 2019;16(1):194. DOI: 10.1186/s12974-019-1595-0.
  116. Li S, Liu W, Wang JL, et al. The role of TNF-a, IL-6, IL-10, and GDNF in neuronal apoptosis in neonatal rat with hypoxic-ischemic encephalopathy. Eur Rev Med Pharmacol Sci 2014;18(6):905–909. PMID: 24706318.
  117. Yun JH, Han MH, Jeong HS, et al. Angiopoietin 1 attenuates interleukin-6–induced endothelial cell permeability through SHP-1. Biochem Biophys Res Commun 2019;518(2):286–293. DOI: 10.1016/j.bbrc.2019.08.048.
  118. Muramatsu K, Fukuda A, Togari H, et al. Vulnerability to cerebral hypoxic-ischemic insult in neonatal but not in adult rats is in parallel with disruption of the blood-brain barrier. Stroke 1997;28(11): 2281–2289. DOI: 10.1161/01.str.28.11.2281.
  119. Penn JS, Henry MM, Wall PT, et al. The range of PaO2 variation determines the severity of oxygen-induced retinopathy in newborn rats. Invest Ophthalmol Vis Sci 1995;36(10):2063–2070. PMID: 7657545.
  120. Connor KM, Krah NM, Dennison RJ, et al. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat Protoc 2009;4(11):1565. DOI: 10.1038/nprot.2009.187.
  121. Mezu-Ndubuisi OJ. In vivo angiography quantifies oxygen-induced retinopathy vascular recovery. Optom Vis Sci 2016;93(10):1268–1279. DOI: 10.1097/OPX.0000000000000941.
  122. Ren Y, Chan HM, Li Z, et al. Upregulation of macrophage migration inhibitory factor contributes to induced N-Myc expression by the activation of ERK signaling pathway and increased expression of interleukin-8 and VEGF in neuroblastoma. Oncogene 2004;23(23):4146–4154. DOI: 10.1038/sj.onc.1207490.
  123. Wang J, Lin J, Kaiser U, et al. Absence of macrophage migration inhibitory factor reduces proliferative retinopathy in a mouse model. Acta Diabetol 2017;54(4):383–392. DOI: 10.1007/s00592-016-0956-8.
  124. Pierce EA, Foley ED, Smith LE. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol 1996;114(10):1219–1228. DOI: 10.1001/archopht.1996.01100140419009.
  125. Shih SC, Ju M, Liu N, et al. Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity. J Clin Invest 2003;112(1):50–57. DOI: 10.1172/JCI17808.
  126. Mezu-Ndubuisi OJ, Wang Y, Schoephoerster J, et al. Intravitreal delivery of VEGF-A165–loaded PLGA microparticles reduces retinal vaso-obliteration in an in vivo mouse model of retinopathy of prematurity. Curr Eye Res 2019;44(3):275–286. DOI: 10.1080/02713683.2018.1542736.
  127. Cayabyab R, Ramanathan R. Retinopathy of prematurity: therapeutic strategies based on pathophysiology. Neonatology 2016;109(4): 369–376. DOI: 10.1159/000444901.
  128. Smith L, Wesolowski E, McLellan A, et al. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 1994;35(1):101–111. PMID: 7507904.
  129. Stahl A, Connor KM, Sapieha P, et al. The mouse retina as an angiogenesis model. Invest Ophthalmol Vis Sci 2010;51(6):2813–2826. DOI: 10.1167/iovs.10-5176.
  130. Mezu-Ndubuisi OJ, Teng P, Wanek J, et al. In vivo retinal vascular oxygen tension imaging and fluorescein angiography in the mouse model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 2013;54(10):6968–6972. DOI: 10.1167/iovs.13-12126.
  131. Dailey WA, Drenser KA, Wong SC, et al. Norrin treatment improves ganglion cell survival in an oxygen-induced retinopathy model of retinal ischemia. Exp Eye Res 2017;164:129–138. DOI: 10.1016/j.exer.2017.08.012.
  132. Mezu-Ndubuisi OJ, Wanek J, Chau FY, et al. Correspondence of retinal thinning and vasculopathy in mice with oxygen-induced retinopathy. Exp Eye Res 2014;122:119–122. DOI: 10.1016/j.exer.2014.03.010.
  133. Mezu-Ndubuisi OJ, Taylor LK, Schoephoerster JA. Simultaneous fluorescein angiography and spectral domain optical coherence tomography correlate retinal thickness changes to vascular abnormalities in an in vivo mouse model of retinopathy of prematurity. J Ophthalmol 2017;2017:9620876. DOI: 10.1155/2017/9620876.
  134. Mezu-Ndubuisi OJ, Adams T, Taylor LK, et al. Simultaneous assessment of aberrant retinal vascularization, thickness, and function in an in vivo mouse oxygen-induced retinopathy model. Eye 2019;33(3): 363–373. DOI: 10.1038/s41433-018-0205-1.
  135. Mitton K, Deshpande M, Wong SC, et al. Retinal plasticity: functional recovery after bipolar cell loss in the oxygen induced retinopathy model. BioRxiv 2019. DOI: 10.1101/2019.12.12.874271.
  136. Mezu-Ndubuisi OJ, Macke EL, Kalavacherla R, et al. Long-term evaluation of retinal morphology and function in a mouse model of oxygen-induced retinopathy. Mol Vis 2020;26:257. PMID: 32256029.
  137. Mezu-Ndubuisi OJ, Maheshwari A. Role of macrophages in fetal development and perinatal disorders. Pediatr Res 2021;90(3):1–13. DOI: 10.1038/s41390-020-01209-4.
  138. Abu El-Asrar AM, Ahmad A, Allegaert E, et al. Interleukin-11 overexpression and M2 macrophage density are associated with angiogenic activity in proliferative diabetic retinopathy. Ocul Immunol Inflamm 2020;28(4):575–588. DOI: 10.1080/09273948.2019. 1616772.
  139. Mezu-Ndubuisi OJ, Maheshwari A. The role of integrins in inflammation and angiogenesis. Pediatr Res 2021;89(7):1619–1626. DOI: 10.1038/s41390-020-01177-9.
  140. Senger DR, Claffey KP, Benes JE, et al. Angiogenesis promoted by vascular endothelial growth factor: regulation through α1β1 and α2β1 integrins. Proc Natl Acad Sci 1997;94(25):13612–13617. DOI: 10.1073/pnas.94.25.13612.
  141. Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998;125(9):1591–1598. DOI: 10.1242/dev. 125.9.1591.
  142. Jamali N, Song YS, Sorenson CM, et al. 1,25 (OH) 2D3 regulates the proangiogenic activity of pericyte through VDR-mediated modulation of VEGF production and signaling of VEGF and PDGF receptors. FASEB Bioadv 2019;1(7):415–434. DOI: 10.1096/fba.2018-00067.
  143. Liang W, Jiang L. Relationship between expression of angiopoietin-2 and retinal vascular development in hyperoxic rats. Chin J Pediatr 2009;47(3):204–208.
  144. Park YJ, Woo SJ, Kim YM, et al. Immune and inflammatory proteins in cord blood as predictive biomarkers of retinopathy of prematurity in preterm infants. Invest Ophthalmol Vis Sci 2019;60(12):3813–3820. DOI: 10.1167/iovs.19-27258.
  145. Woo SJ, Park JY, Hong S, et al. Inflammatory and angiogenic mediators in amniotic fluid are associated with the development of retinopathy of prematurity in preterm infants. Invest Ophthalmol Vis Sci 2020;61(5):42–42. DOI: 10.1167/iovs.61.5.42.
  146. Pieh C, Agostini H, Buschbeck C, et al. VEGF-A, VEGFR-1, VEGFR-2 and Tie2 levels in plasma of premature infants: relationship to retinopathy of prematurity. Br J Ophthalmol 2008;92(5):689–693. DOI: 10.1136/bjo.2007.128371.
  147. Jobe A, Bancalari E. NICHD/NHLBI. In ORD Workshop Summary. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163(7):1723–1729. DOI: 10.1164/ajrccm.163.7.2011060.
  148. Abman SH. Bronchopulmonary dysplasia: “a vascular hypothesis”. Am J Respir Crit Care Med 2001;164(10):1755–1756. DOI: 10.1164/ajrccm.164.10.2109111c.
  149. Northway Jr WH, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease: bronchopulmonary dysplasia. New Engl J Med 1967;276(7):357–368. DOI: 10.1056/NEJM196702162760701.
  150. McEvoy CT, Jain L, Schmidt B, et al. Bronchopulmonary dysplasia: NHLBI workshop on the primary prevention of chronic lung diseases. Ann Am Thorac Soc 2014;11(Suppl 3):S146–S153. DOI: 10.1513/AnnalsATS.201312-424LD.
  151. Orfanos S, Mavrommati I, Korovesi I, et al. Pulmonary endothelium in acute lung injury: from basic science to the critically ill. In: Applied physiology in intensive care medicine. Springer; 2006. p. 171–183.
  152. Bhatt AJ, Pryhuber GS, Huyck H, et al. Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. Am j Respir Crit Care Med 2001;164(10):1971–1980. DOI: 10.1164/ajrccm.164.10.2101140.
  153. Jakkula M, Le Cras TD, Gebb S, et al. Inhibition of angiogenesis decreases alveolarization in the developing rat lung. Am J Physiol Lung Cell Mol Physiol 2000;279(3):L600–L607. DOI: 10.1152/ajplung.2000.279.3.L600.
  154. Syed M, Das P, Pawar A, et al. Hyperoxia causes miR-34a-mediated injury via angiopoietin-1 in neonatal lungs. Nat Commun 2017;8(1): 1–17. DOI: 10.1038/s41467-017-01349-y.
  155. Sahni M, Yeboah B, Das P, et al. Novel biomarkers of bronchopulmonary dysplasia and bronchopulmonary dysplasia-associated pulmonary hypertension. J Perinatol 2020;40(11):1634–1643. DOI: 10.1038/s41372-020-00788-8.
  156. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004;109(2):159–165. DOI: 10.1161/01.CIR.0000102381.57477.50.
  157. Aird WC. Endothelial cell dynamics and complexity theory. Crit Care Med 2002;30(5):S180–S185. DOI: 10.1097/00003246-200205001-00002.
  158. Nankervis CA, Reber KM, Nowicki PT. Age-dependent changes in the postnatal intestinal microcirculation. Microcirculation 2001;8(6): 377–387. DOI: 10.1038/sj/mn/7800110.
  159. Ito Y, Doelle SM, Clark JA, et al. Intestinal microcirculatory dysfunction during the development of experimental necrotizing enterocolitis. Pediatr Res 2007;61(2):180–184. DOI: 10.1203/pdr.0b013e31802d77db.
  160. Sabnis A, Carrasco R, Liu SXL, et al. Intestinal vascular endothelial growth factor is decreased in necrotizing enterocolitis. Neonatology 2015;107(3):191–198. DOI: 10.1159/000368879.
  161. Yan X, Managlia E, Liu SX, et al. Lack of VEGFR2 signaling causes maldevelopment of the intestinal microvasculature and facilitates necrotizing enterocolitis in neonatal mice. Am J Physiol Gastrointest Liver Physiol 2016;310(9):G716–G725. DOI: 10.1152/ajpgi.00273.2015.
  162. Bowker RM, Yan X, Managlia E, et al. Dimethyloxalylglycine preserves the intestinal microvasculature and protects against intestinal injury in a neonatal mouse NEC model: role of VEGF signaling. Pediatr Res 2018;83(2):545–553. DOI: 10.1038/pr.2017.219.
  163. Conger JD, Robinette JB, Hammond WS. Differences in vascular reactivity in models of ischemic acute renal failure. Kidney Int 1991;39(6):1087–1097. DOI: 10.1038/ki.1991.138.
  164. Sutton TA, Fisher CJ, Molitoris BA. Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int 2002;62(5):1539–1549. DOI: 10.1046/j.1523-1755.2002.00631.x.
  165. Kwon O, Phillips CL, Molitoris BA. Ischemia induces alterations in actin filaments in
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.