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Angiogenesis

, Volume 21, Issue 2, pp 335–347 | Cite as

Glomerular endothelial cell maturation depends on ADAM10, a key regulator of Notch signaling

  • Gregory Farber
  • Romulo Hurtado
  • Sarah Loh
  • Sébastien Monette
  • James Mtui
  • Raphael Kopan
  • Susan Quaggin
  • Catherine Meyer-Schwesinger
  • Doris Herzlinger
  • Rizaldy P. Scott
  • Carl P. Blobel
Original Paper
First Online:
Received:
Accepted:

Abstract

The principal function of glomeruli is to filter blood through a highly specialized filtration barrier consisting of a fenestrated endothelium, the glomerular basement membrane and podocyte foot processes. Previous studies have uncovered a crucial role of endothelial a disintegrin and metalloprotease 10 (ADAM10) and Notch signaling in the development of glomeruli, yet the resulting defects have not been further characterized nor understood in the context of kidney development. Here, we used several different experimental approaches to analyze the kidneys and glomeruli from mice lacking ADAM10 in endothelial cells (A10ΔEC mice). Scanning electron microscopy of glomerular casts demonstrated enlarged vascular diameter and increased intussusceptive events in A10ΔEC glomeruli compared to controls. Consistent with these findings, genes known to regulate vessel caliber (Apln, AplnR and Vegfr3) are significantly upregulated in A10ΔEC glomeruli. Moreover, transmission electron microscopy revealed the persistence of diaphragms in the fenestrae of A10ΔEC glomerular endothelial cells, which was corroborated by the elevated expression of the protein PLVAP/PV-1, an integral component of fenestral diaphragms. Analysis of gross renal vasculature by light sheet microscopy showed no major alteration of the branching pattern, indicating a localized importance of ADAM10 in the glomerular endothelium. Since intussusceptions and fenestrae with diaphragms are normally found in developing, but not mature glomeruli, our results provide the first evidence for a crucial role of endothelial ADAM10, a key regulator of Notch signaling, in promoting the development and maturation of the glomerular vasculature.

Keywords

Glomeruli Endothelial cells A disintegrin and metalloprotease 10 (ADAM10) Notch Fenestra Diaphragms 
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Notes

Acknowledgements

G. Farber is currently supported by a predoctoral Fellowship from the American Heart Association and was previously supported by Molecular and Cellular Biology T32 training Grant from the National Institutes of Health, 5T32GM008539. These studies were supported in part by the National Institutes of Health R01 Grant GM64750 to CPB. We would like to thank Dr. Alison North and Rockefeller University’s Bio-Imaging Resource Center for the training and usage of the light sheet microscopy and image analysis, Dr. Kunihiro Uryu and Rockefeller University’s Electron Microscopy Resource Center for training on and usage of scanning electron microscopy. A special thanks to Lee Cohen Gould and Juan Jimenez at the Weill Cornell Medicine Imaging Core Facility for the preparation of the transmission electron microscopy samples and training, and Dr. Katia Manova, Ning Fan and Afsar Barlas from the Molecular Cytology Core Facility at Memorial Sloan-Kettering Cancer Center (supported by the Cancer Center Support Grant P30CA008748). S. Monette and the Laboratory of Comparative Pathology are also supported in part by Cancer Center Support Grant P30CA008748.

Author’s Contribution

GF and CB conceived of this study, RH, SL, SM, JM and CMS performed experiments and interpreted the results, GF drafted the manuscript, all authors contributed to editing, and GF and RPS prepared the figures.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary material 1 (PDF 2766 kb)
10456_2018_9599_MOESM2_ESM.avi (6.7 mb)
Supplementary material 2 (AVI 6840 kb)

References

  1. 1.
    Scott RP, Quaggin SE (2015) Review series: the cell biology of renal filtration. J Cell Biol 209(2):199–210.  https://doi.org/10.1083/jcb.201410017 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Eremina V, Baelde HJ, Quaggin SE (2007) Role of the VEGF-A signaling pathway in the glomerulus: evidence for crosstalk between components of the glomerular filtration barrier. Nephron Physiol 106(2):p32–p37.  https://doi.org/10.1159/000101798 CrossRefPubMedGoogle Scholar
  3. 3.
    Vaughan MR, Quaggin SE (2008) How do mesangial and endothelial cells form the glomerular tuft? J Am Soc Nephrol 19(1):24–33.  https://doi.org/10.1681/ASN.2007040471 CrossRefPubMedGoogle Scholar
  4. 4.
    Ichimura K, Stan RV, Kurihara H, Sakai T (2008) Glomerular endothelial cells form diaphragms during development and pathologic conditions. J Am Soc Nephrol 19(8):1463–1471.  https://doi.org/10.1681/ASN.2007101138 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Satchell SC, Braet F (2009) Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier. Am J Physiol Renal Physiol 296(5):F947–F956.  https://doi.org/10.1152/ajprenal.90601.2008 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Stan RV (2007) Endothelial stomatal and fenestral diaphragms in normal vessels and angiogenesis. J Cell Mol Med 11(4):621–643.  https://doi.org/10.1111/j.1582-4934.2007.00075.x CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Wang Y, Rattner A, Zhou Y, Williams J, Smallwood PM, Nathans J (2012) Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity. Cell 151(6):1332–1344.  https://doi.org/10.1016/j.cell.2012.10.042 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Covassin L, Amigo JD, Suzuki K, Teplyuk V, Straubhaar J, Lawson ND (2006) Global analysis of hematopoietic and vascular endothelial gene expression by tissue specific microarray profiling in zebrafish. Dev Biol 299(2):551–562.  https://doi.org/10.1016/j.ydbio.2006.08.020 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Chang AC, Fu Y, Garside VC, Niessen K, Chang L, Fuller M, Setiadi A, Smrz J, Kyle A, Minchinton A, Marra M, Hoodless PA, Karsan A (2011) Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase. Dev Cell 21(2):288–300.  https://doi.org/10.1016/j.devcel.2011.06.022 CrossRefPubMedGoogle Scholar
  10. 10.
    Mintet E, Lavigne J, Paget V, Tarlet G, Buard V, Guipaud O, Sabourin JC, Iruela-Arispe ML, Milliat F, Francois A (2017) Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice. Sci Rep 7(1):4933.  https://doi.org/10.1038/s41598-017-05389-8 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Quaggin SE, Kreidberg JA (2008) Development of the renal glomerulus: good neighbors and good fences. Development 135(4):609–620.  https://doi.org/10.1242/dev.001081 CrossRefPubMedGoogle Scholar
  12. 12.
    Boyle SC, Liu Z, Kopan R (2014) Notch signaling is required for the formation of mesangial cells from a stromal mesenchyme precursor during kidney development. Development 141(2):346–354.  https://doi.org/10.1242/dev.100271 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Cheng HT, Kopan R (2005) The role of Notch signaling in specification of podocyte and proximal tubules within the developing mouse kidney. Kidney Int 68(5):1951–1952.  https://doi.org/10.1111/j.1523-1755.2005.00627.x CrossRefPubMedGoogle Scholar
  14. 14.
    Glomski K, Monette S, Manova K, De Strooper B, Saftig P, Blobel CP (2011) Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures. Blood 118(4):1163–1174.  https://doi.org/10.1182/blood-2011-04-348557 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bozkulak EC, Weinmaster G (2009) Selective use of ADAM10 and ADAM17 in activation of Notch1 signaling. Mol Cell Biol 29(21):5679–5695CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    van Tetering G, van Diest P, Verlaan I, van der Wall E, Kopan R, Vooijs M (2009) Metalloprotease ADAM10 is required for Notch1 site 2 cleavage. J Biol Chem 284(45):31018–31027CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rooke J, Pan D, Xu T, Rubin GM (1996) KUZ, a conserved metalloprotease-disintegrin protein with two roles in Drosophila neurogenesis. Science 273(5279):1227–1230CrossRefPubMedGoogle Scholar
  18. 18.
    Hartmann D, de Strooper B, Serneels L, Craessaerts K, Herreman A, Annaert W, Umans L, Lubke T, Lena Illert A, von Figura K, Saftig P (2002) The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum Mol Genet 11(21):2615–2624CrossRefPubMedGoogle Scholar
  19. 19.
    Alabi RO, Glomski K, Haxaire C, Weskamp G, Monette S, Blobel CP (2016) ADAM10-dependent signaling through Notch1 and Notch4 controls development of organ-specific vascular beds. Circ Res 119(4):519–531.  https://doi.org/10.1161/CIRCRESAHA.115.307738 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Gridley T (2007) Notch signaling in vascular development and physiology. Development 134(15):2709–2718CrossRefPubMedGoogle Scholar
  21. 21.
    Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C (2007) Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445(7129):776–780CrossRefPubMedGoogle Scholar
  22. 22.
    Hofmann JJ, Iruela-Arispe ML (2007) Notch signaling in blood vessels: Who is talking to whom about what? Circ Res 100(11):1556–1568.  https://doi.org/10.1161/01.RES.0000266408.42939.e4 CrossRefPubMedGoogle Scholar
  23. 23.
    Roca C, Adams RH (2007) Regulation of vascular morphogenesis by Notch signaling. Genes Dev 21(20):2511–2524CrossRefPubMedGoogle Scholar
  24. 24.
    Kusumbe AP, Ramasamy SK, Adams RH (2014) Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507(7492):323–328.  https://doi.org/10.1038/nature13145 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ramasamy SK, Kusumbe AP, Wang L, Adams RH (2014) Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507(7492):376–380.  https://doi.org/10.1038/nature13146 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Cuervo H, Nielsen CM, Simonetto DA, Ferrell L, Shah VH, Wang RA (2016) Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice. Hepatology.  https://doi.org/10.1002/hep.28713 PubMedPubMedCentralGoogle Scholar
  27. 27.
    Blanco R, Gerhardt H (2013) VEGF and Notch in tip and stalk cell selection. Cold Spring Harb Perspect Med 3(1):a006569.  https://doi.org/10.1101/cshperspect.a006569 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Takemoto M, Asker N, Gerhardt H, Lundkvist A, Johansson BR, Saito Y, Betsholtz C (2002) A new method for large scale isolation of kidney glomeruli from mice. Am J Pathol 161(3):799–805.  https://doi.org/10.1016/S0002-9440(10)64239-3 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Stan RV, Tkachenko E, Niesman IR (2004) PV1 is a key structural component for the formation of the stomatal and fenestral diaphragms. Mol Biol Cell 15(8):3615–3630.  https://doi.org/10.1091/mbc.E03-08-0593 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ioannidou S, Deinhardt K, Miotla J, Bradley J, Cheung E, Samuelsson S, Ng YS, Shima DT (2006) An in vitro assay reveals a role for the diaphragm protein PV-1 in endothelial fenestra morphogenesis. Proc Natl Acad Sci USA 103(45):16770–16775.  https://doi.org/10.1073/pnas.0603501103 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kidoya H, Ueno M, Yamada Y, Mochizuki N, Nakata M, Yano T, Fujii R, Takakura N (2008) Spatial and temporal role of the apelin/APJ system in the caliber size regulation of blood vessels during angiogenesis. EMBO J 27(3):522–534.  https://doi.org/10.1038/sj.emboj.7601982 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Takakura N, Kidoya H (2009) Maturation of blood vessels by haematopoietic stem cells and progenitor cells: involvement of apelin/APJ and angiopoietin/Tie2 interactions in vessel caliber size regulation. Thromb Haemost 101(6):999–1005PubMedGoogle Scholar
  33. 33.
    Kidoya H, Takakura N (2012) Biology of the apelin-APJ axis in vascular formation. J Biochem 152(2):125–131.  https://doi.org/10.1093/jb/mvs071 CrossRefPubMedGoogle Scholar
  34. 34.
    Shawber CJ, Funahashi Y, Francisco E, Vorontchikhina M, Kitamura Y, Stowell SA, Borisenko V, Feirt N, Podgrabinska S, Shiraishi K, Chawengsaksophak K, Rossant J, Accili D, Skobe M, Kitajewski J (2007) Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. J Clin Invest 117(11):3369–3382.  https://doi.org/10.1172/JCI24311 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Takabatake Y, Sugiyama T, Kohara H, Matsusaka T, Kurihara H, Koni PA, Nagasawa Y, Hamano T, Matsui I, Kawada N, Imai E, Nagasawa T, Rakugi H, Isaka Y (2009) The CXCL12 (SDF-1)/CXCR4 axis is essential for the development of renal vasculature. J Am Soc Nephrol 20(8):1714–1723.  https://doi.org/10.1681/ASN.2008060640 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Makanya AN, Stauffer D, Ribatti D, Burri PH, Djonov V (2005) Microvascular growth, development, and remodeling in the embryonic avian kidney: the interplay between sprouting and intussusceptive angiogenic mechanisms. Microsc Res Tech 66(6):275–288.  https://doi.org/10.1002/jemt.20169 CrossRefPubMedGoogle Scholar
  37. 37.
    Notoya M, Shinosaki T, Kobayashi T, Sakai T, Kurihara H (2003) Intussusceptive capillary growth is required for glomerular repair in rat Thy-1.1 nephritis. Kidney Int 63(4):1365–1373.  https://doi.org/10.1046/j.1523-1755.2003.00876.x CrossRefPubMedGoogle Scholar
  38. 38.
    Foster RR, Slater SC, Seckley J, Kerjaschki D, Bates DO, Mathieson PW, Satchell SC (2008) Vascular endothelial growth factor-C, a potential paracrine regulator of glomerular permeability, increases glomerular endothelial cell monolayer integrity and intracellular calcium. Am J Pathol 173(4):938–948.  https://doi.org/10.2353/ajpath.2008.070416 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Benedito R, Rocha SF, Woeste M, Zamykal M, Radtke F, Casanovas O, Duarte A, Pytowski B, Adams RH (2012) Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature 484(7392):110–114.  https://doi.org/10.1038/nature10908 CrossRefPubMedGoogle Scholar
  40. 40.
    Coon BG, Baeyens N, Han J, Budatha M, Ross TD, Fang JS, Yun S, Thomas JL, Schwartz MA (2015) Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex. J Cell Biol 208(7):975–986.  https://doi.org/10.1083/jcb.201408103 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Djonov VG, Kurz H, Burri PH (2002) Optimality in the developing vascular system: branching remodeling by means of intussusception as an efficient adaptation mechanism. Dev Dyn 224(4):391–402.  https://doi.org/10.1002/dvdy.10119 CrossRefPubMedGoogle Scholar
  42. 42.
    Wasserman SM, Mehraban F, Komuves LG, Yang RB, Tomlinson JE, Zhang Y, Spriggs F, Topper JN (2002) Gene expression profile of human endothelial cells exposed to sustained fluid shear stress. Physiol Genomics 12(1):13–23.  https://doi.org/10.1152/physiolgenomics.00102.2002 CrossRefPubMedGoogle Scholar
  43. 43.
    Kim YH, Hu H, Guevara-Gallardo S, Lam MT, Fong SY, Wang RA (2008) Artery and vein size is balanced by Notch and ephrin B2/EphB4 during angiogenesis. Development 135(22):3755–3764.  https://doi.org/10.1242/dev.022475 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Renier N, Adams EL, Kirst C, Wu Z, Azevedo R, Kohl J, Autry AE, Kadiri L, Umadevi Venkataraju K, Zhou Y, Wang VX, Tang CY, Olsen O, Dulac C, Osten P, Tessier-Lavigne M (2016) Mapping of brain activity by automated volume analysis of immediate early genes. Cell 165(7):1789–1802.  https://doi.org/10.1016/j.cell.2016.05.007 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Meyer TN, Schwesinger C, Wahlefeld J, Dehde S, Kerjaschki D, Becker JU, Stahl RA, Thaiss F (2007) A new mouse model of immune-mediated podocyte injury. Kidney Int 72(7):841–852.  https://doi.org/10.1038/sj.ki.5002450 CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Physiology, Biophysics and Systems BiologyWeill Cornell MedicineNew YorkUSA
  2. 2.Arthritis and Tissue Degeneration ProgramHospital for Special SurgeryNew YorkUSA
  3. 3.Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer CenterThe Rockefeller University, Weill Cornell MedicineNew YorkUSA
  4. 4.Division of Developmental Biology, Cincinnati Children’s Hospital Medical CenterUniversity of Cincinnati College of MedicineCincinnatiUSA
  5. 5.Feinberg Cardiovascular Research Institute and Division of Nephrology and HypertensionNorthwestern UniversityChicagoUSA
  6. 6.Department of NephrologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  7. 7.Institute for Advanced StudyTechnical University MunichMunichGermany

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