Angiogenesis

pp 1–18 | Cite as

Spatiotemporal heterogeneity and patterning of developing renal blood vessels

  • Edward Daniel
  • D. Berfin Azizoglu
  • Anne R. Ryan
  • Tezin A. Walji
  • Christopher P. Chaney
  • Gabrielle I. Sutton
  • Thomas J. Carroll
  • Denise K. Marciano
  • Ondine Cleaver
Original Paper

Abstract

The kidney vasculature facilitates the excretion of wastes, the dissemination of hormones, and the regulation of blood chemistry. To carry out these diverse functions, the vasculature is regionalized within the kidney and along the nephron. However, when and how endothelial regionalization occurs remains unknown. Here, we examine the developing kidney vasculature to assess its 3-dimensional structure and transcriptional heterogeneity. First, we observe that endothelial cells (ECs) grow coordinately with the kidney bud as early as E10.5, and begin to show signs of specification by E13.5 when the first arteries can be identified. We then focus on how ECs pattern and remodel with respect to the developing nephron and collecting duct epithelia. ECs circumscribe nephron progenitor populations at the distal tips of the ureteric bud (UB) tree and form stereotyped cruciform structures around each tip. Beginning at the renal vesicle (RV) stage, ECs form a continuous plexus around developing nephrons. The endothelial plexus envelops and elaborates with the maturing nephron, becoming preferentially enriched along the early distal tubule. Lastly, we perform transcriptional and immunofluorescent screens to characterize spatiotemporal heterogeneity in the kidney vasculature and identify novel regionally enriched genes. A better understanding of development of the kidney vasculature will help instruct engineering of properly vascularized ex vivo kidneys and evaluate diseased kidneys.

Keywords

Endothelium Epithelium Blood vessel Nephron Vascular patterning Endothelial cell heterogeneity 

Notes

Acknowledgements

We thank Janet Rossant for the Flk1-eGFP mouse line, as well as members of the Cleaver lab, including Caitlin Braitsch, Xiaowu Gu, and David Barry, for discussions and critical reading of the manuscript. We thank the Genepaint.org database for in situ hybridization data (where noted).

Author contributions

Experiments were performed by ED, DBA, ARR, TAW, CC, and GISTJC, DKM, and OC supervised the project and contributed to analysis. ED and OC wrote the text of this article with input from co-authors.

Compliance with ethical standards

Conflict of interest

The authors declare no competing or financial interests.

Supplementary material

10456_2018_9612_MOESM1_ESM.pdf (1.3 mb)
Supplementary material 1 (PDF 1354 kb)
10456_2018_9612_MOESM2_ESM.pdf (37 kb)
Supplementary material 2 (PDF 37 kb)
10456_2018_9612_MOESM3_ESM.pdf (39 kb)
Supplementary material 3 (PDF 39 kb)
10456_2018_9612_MOESM4_ESM.mp4 (2.2 mb)
Supplementary material 4 (MP4 2269 kb)
10456_2018_9612_MOESM5_ESM.mp4 (2.9 mb)
Supplementary material 5 (MP4 2931 kb)
10456_2018_9612_MOESM6_ESM.mp4 (4.3 mb)
Supplementary material 6 (MP4 4372 kb)
10456_2018_9612_MOESM7_ESM.mp4 (4.7 mb)
Supplementary material 7 (MP4 4846 kb)
10456_2018_9612_MOESM8_ESM.mp4 (894 kb)
Supplementary material 8 (MP4 894 kb)
10456_2018_9612_MOESM9_ESM.mp4 (978 kb)
Supplementary material 9 (MP4 978 kb)
10456_2018_9612_MOESM10_ESM.mp4 (1 mb)
Supplementary material 10 (MP4 1065 kb)
10456_2018_9612_MOESM11_ESM.csv (3 kb)
Supplementary material 11 (CSV 4 kb)

References

  1. 1.
    Cleaver O, Tonissen KF, Saha MS, Krieg PA (1997) Neovascularization of the Xenopus embryo. Dev Dyn 210(1):66–77CrossRefPubMedGoogle Scholar
  2. 2.
    Herbert SP, Huisken J, Kim TN, Feldman ME, Houseman BT, Wang RA, Shokat KM, Stainier DY (2009) Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation. Science 326(5950):294–298.  https://doi.org/10.1126/science.1178577 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Coultas L, Nieuwenhuis E, Anderson GA, Cabezas J, Nagy A, Henkelman RM, Hui CC, Rossant J (2010) Hedgehog regulates distinct vascular patterning events through VEGF-dependent and -independent mechanisms. Blood 116(4):653–660.  https://doi.org/10.1182/blood-2009-12-256644 CrossRefPubMedGoogle Scholar
  4. 4.
    Drake CJ, Fleming PA (2000) Vasculogenesis in the day 6.5 to 9.5 mouse embryo. Blood 95(5):1671–1679PubMedGoogle Scholar
  5. 5.
    Azizoglu DB, Chong DC, Villasenor A, Magenheim J, Barry DM, Lee S, Marty-Santos L, Fu S, Dor Y, Cleaver O (2016) Vascular development in the vertebrate pancreas. Dev Biol 420(1):67–78.  https://doi.org/10.1016/j.ydbio.2016.10.009 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Oxburgh L, Carroll TJ, Cleaver O, Gossett DR, Hoshizaki DK, Hubbell JA, Humphreys BD, Jain S, Jensen J, Kaplan DL, Kesselman C, Ketchum CJ, Little MH, McMahon AP, Shankland SJ, Spence JR, Valerius MT, Wertheim JA, Wessely O, Zheng Y, Drummond IA (2017) (Re)building a kidney. J Am Soc Nephrol 28(5):1370–1378.  https://doi.org/10.1681/ASN.2016101077 CrossRefPubMedGoogle Scholar
  7. 7.
    O’Brien LL, McMahon AP (2014) Induction and patterning of the metanephric nephron. Semin Cell Dev Biol 36:31–38.  https://doi.org/10.1016/j.semcdb.2014.08.014 CrossRefPubMedGoogle Scholar
  8. 8.
    Yang Z, Zimmerman S, Brakeman PR, Beaudoin GM 3rd, Reichardt LF, Marciano DK (2013) De novo lumen formation and elongation in the developing nephron: a central role for afadin in apical polarity. Development 140(8):1774–1784.  https://doi.org/10.1242/dev.087957 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gao L, Yang Z, Hiremath C, Zimmerman SE, Long B, Brakeman PR, Mostov KE, Bryant DM, Luby-Phelps K, Marciano DK (2017) Afadin orients cell division to position the tubule lumen in developing renal tubules. Development 144(19):3511–3520.  https://doi.org/10.1242/dev.148908 CrossRefPubMedGoogle Scholar
  10. 10.
    Robert B, St John PL, Abrahamson DR (1998) Direct visualization of renal vascular morphogenesis in Flk1 heterozygous mutant mice. Am J Physiol 275(1 Pt 2):F164–F172PubMedGoogle Scholar
  11. 11.
    Tufro A, Norwood VF, Carey RM, Gomez RA (1999) Vascular endothelial growth factor induces nephrogenesis and vasculogenesis. J Am Soc Nephrol 10(10):2125–2134PubMedGoogle Scholar
  12. 12.
    Munro DAD, Hohenstein P, Davies JA (2017) Cycles of vascular plexus formation within the nephrogenic zone of the developing mouse kidney. Sci Rep 7(1):3273.  https://doi.org/10.1038/s41598-017-03808-4 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    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
  14. 14.
    Gao X, Chen X, Taglienti M, Rumballe B, Little MH, Kreidberg JA (2005) Angioblast-mesenchyme induction of early kidney development is mediated by Wt1 and Vegfa. Development 132(24):5437–5449.  https://doi.org/10.1242/dev.02095 CrossRefPubMedGoogle Scholar
  15. 15.
    Munro DAD, Hohenstein P, Coate TM, Davies JA (2017) Refuting the hypothesis that semaphorin-3f/neuropilin-2 exclude blood vessels from the cap mesenchyme in the developing kidney. Dev Dyn 246(12):1047–1056.  https://doi.org/10.1002/dvdy.24592 CrossRefPubMedGoogle Scholar
  16. 16.
    Hurtado R, Zewdu R, Mtui J, Liang C, Aho R, Kurylo C, Selleri L, Herzlinger D (2015) Pbx1-dependent control of VMC differentiation kinetics underlies gross renal vascular patterning. Development 142(15):2653–2664.  https://doi.org/10.1242/dev.124776 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Villasenor A, Chong DC, Cleaver O (2008) Biphasic Ngn3 expression in the developing pancreas. Dev Dyn 237(11):3270–3279.  https://doi.org/10.1002/dvdy.21740 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Acar M, Kocherlakota KS, Murphy MM, Peyer JG, Oguro H, Inra CN, Jaiyeola C, Zhao Z, Luby-Phelps K, Morrison SJ (2015) Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 526(7571):126–130.  https://doi.org/10.1038/nature15250 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C (2017) Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods 14(4):417–419.  https://doi.org/10.1038/nmeth.4197 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Soneson C, Love MI, Robinson MD (2015) Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. F1000Res 4:1521.  https://doi.org/10.12688/f1000research.7563.2 CrossRefPubMedGoogle Scholar
  21. 21.
    Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15(12):550.  https://doi.org/10.1186/s13059-014-0550-8 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Langfelder P, Horvath S (2008) WGCNA: an R package for weighted correlation network analysis. BMC Bioinform 9:559.  https://doi.org/10.1186/1471-2105-9-559 CrossRefGoogle Scholar
  23. 23.
    Ema M, Takahashi S, Rossant J (2006) Deletion of the selection cassette, but not cis-acting elements, in targeted Flk1-lacZ allele reveals Flk1 expression in multipotent mesodermal progenitors. Blood 107(1):111–117.  https://doi.org/10.1182/blood-2005-05-1970 CrossRefPubMedGoogle Scholar
  24. 24.
    Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376(6535):62–66CrossRefPubMedGoogle Scholar
  25. 25.
    Moyon D, Pardanaud L, Yuan L, Breant C, Eichmann A (2001) Plasticity of endothelial cells during arterial-venous differentiation in the avian embryo. Development 128(17):3359–3370PubMedGoogle Scholar
  26. 26.
    Rymer C, Paredes J, Halt K, Schaefer C, Wiersch J, Zhang G, Potoka D, Vainio S, Gittes GK, Bates CM, Sims-Lucas S (2014) Renal blood flow and oxygenation drive nephron progenitor differentiation. Am J Physiol Renal Physiol 307(3):F337–F345.  https://doi.org/10.1152/ajprenal.00208.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Chong DC, Koo Y, Xu K, Fu S, Cleaver O (2011) Stepwise arteriovenous fate acquisition during mammalian vasculogenesis. Dev Dyn 240(9):2153–2165.  https://doi.org/10.1002/dvdy.22706 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Klagsbrun M, Takashima S, Mamluk R (2002) The role of neuropilin in vascular and tumor biology. Adv Exp Med Biol 515:33–48CrossRefPubMedGoogle Scholar
  29. 29.
    dela Paz NG, dela D’Amore PA (2009) Arterial versus venous endothelial cells. Cell Tissue Res 335(1):5–16.  https://doi.org/10.1007/s00441-008-0706-5 CrossRefGoogle Scholar
  30. 30.
    Villasenor A, Wang ZV, Rivera LB, Ocal O, Asterholm IW, Scherer PE, Brekken RA, Cleaver O, Wilkie TM (2010) Rgs16 and Rgs8 in embryonic endocrine pancreas and mouse models of diabetes. Dis Model Mech 3(9–10):567–580.  https://doi.org/10.1242/dmm.003210 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Magenheim J, Ilovich O, Lazarus A, Klochendler A, Ziv O, Werman R, Hija A, Cleaver O, Mishani E, Keshet E, Dor Y (2011) Blood vessels restrain pancreas branching, differentiation and growth. Development 138(21):4743–4752.  https://doi.org/10.1242/dev.066548 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Zeng X, Wert SE, Federici R, Peters KG, Whitsett JA (1998) VEGF enhances pulmonary vasculogenesis and disrupts lung morphogenesis in vivo. Dev Dyn 211(3):215–227CrossRefPubMedGoogle Scholar
  33. 33.
    Lazarus A, Del-Moral PM, Ilovich O, Mishani E, Warburton D, Keshet E (2011) A perfusion-independent role of blood vessels in determining branching stereotypy of lung airways. Development 138(11):2359–2368.  https://doi.org/10.1242/dev.060723 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Costantini F, Kopan R (2010) Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. Dev Cell 18(5):698–712.  https://doi.org/10.1016/j.devcel.2010.04.008 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH, Quaggin SE (2003) Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111(5):707–716CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kitamoto Y, Tokunaga H, Tomita K (1997) Vascular endothelial growth factor is an essential molecule for mouse kidney development: glomerulogenesis and nephrogenesis. J Clin Invest 99(10):2351–2357CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lindstrom NO, Tran T, Guo J, Rutledge E, Parvez RK, Thornton ME, Grubbs B, McMahon JA, McMahon AP (2018) Conserved and divergent molecular and anatomic features of human and mouse nephron patterning. J Am Soc Nephrol.  https://doi.org/10.1681/ASN.2017091036 Google Scholar
  38. 38.
    Yang Z, Zimmerman SE, Tsunezumi J, Braitsch C, Trent C, Bryant DM, Cleaver O, Gonzalez-Manchon C, Marciano DK (2016) Role of CD34 family members in lumen formation in the developing kidney. Dev Biol 418(1):66–74.  https://doi.org/10.1016/j.ydbio.2016.08.009 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lindstrom NO, McMahon JA, Guo J, Tran T, Guo Q, Rutledge E, Parvez RK, Saribekyan G, Schuler RE, Liao C, Kim AD, Abdelhalim A, Ruffins SW, Thornton ME, Basking L, Grubbs B, Kesselman C, McMahon AP (2018) Conserved and divergent features of human and mouse kidney organogenesis. J Am Soc Nephrol.  https://doi.org/10.1681/ASN.2017080887 Google Scholar
  40. 40.
    Lindstrom NO, Guo J, Kim AD, Tran T, Guo Q, De Sena BG, Ransick A, Parvez RK, Thornton ME, Basking L, Grubbs B, McMahon JA, Smith AD, McMahon AP (2018) Conserved and divergent features of mesenchymal progenitor cell types within the cortical nephrogenic niche of the human and mouse kidney. J Am Soc Nephrol.  https://doi.org/10.1681/ASN.2017080890 Google Scholar
  41. 41.
    O’Brien LL, Guo Q, Lee Y, Tran T, Benazet JD, Whitney PH, Valouev A, McMahon AP (2016) Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators. Development 143(4):595–608.  https://doi.org/10.1242/dev.127175 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Hum S, Rymer C, Schaefer C, Bushnell D, Sims-Lucas S (2014) Ablation of the renal stroma defines its critical role in nephron progenitor and vasculature patterning. PLoS ONE 9(2):e88400.  https://doi.org/10.1371/journal.pone.0088400 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Sequeira-Lopez ML, Lin EE, Li M, Hu Y, Sigmund CD, Gomez RA (2015) The earliest metanephric arteriolar progenitors and their role in kidney vascular development. Am J Physiol Regul Integr Comp Physiol 308(2):R138–R149.  https://doi.org/10.1152/ajpregu.00428.2014 CrossRefPubMedGoogle Scholar
  44. 44.
    Nordsletten DA, Blackett S, Bentley MD, Ritman EL, Smith NP (2006) Structural morphology of renal vasculature. Am J Physiol Heart Circ Physiol 291(1):H296–H309.  https://doi.org/10.1152/ajpheart.00814.2005 CrossRefPubMedGoogle Scholar
  45. 45.
    Tufro A (2000) VEGF spatially directs angiogenesis during metanephric development in vitro. Dev Biol 227(2):558–566CrossRefPubMedGoogle Scholar
  46. 46.
    Abrahamson DR (2009) Development of kidney glomerular endothelial cells and their role in basement membrane assembly. Organogenesis 5(1):275–287CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Mazumdar J, O’Brien WT, Johnson RS, LaManna JC, Chavez JC, Klein PS, Simon MC (2010) O2 regulates stem cells through Wnt/beta-catenin signalling. Nat Cell Biol 12(10):1007–1013.  https://doi.org/10.1038/ncb2102 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Culver JC, Vadakkan TJ, Dickinson ME (2013) A specialized microvascular domain in the mouse neural stem cell niche. PLoS ONE 8(1):e53546.  https://doi.org/10.1371/journal.pone.0053546 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, Shima H, Johnson RS, Hirao A, Suematsu M, Suda T (2010) Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7(3):391–402.  https://doi.org/10.1016/j.stem.2010.06.020 CrossRefPubMedGoogle Scholar
  50. 50.
    Kimura W, Xiao F, Canseco DC, Muralidhar S, Thet S, Zhang HM, Abderrahman Y, Chen R, Garcia JA, Shelton JM, Richardson JA, Ashour AM, Asaithamby A, Liang H, Xing C, Lu Z, Zhang CC, Sadek HA (2015) Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart. Nature 523(7559):226–230.  https://doi.org/10.1038/nature14582 CrossRefPubMedGoogle Scholar
  51. 51.
    Saxén L (1987) Vascularization of the nephron. In: Barlow PW, Green PB, Wylie CC (eds) Organogenesis of the kidney. Cambridge University Press, Cambridge, pp 129–142CrossRefGoogle Scholar
  52. 52.
    Molema G, Aird WC (2012) Vascular heterogeneity in the kidney. Semin Nephrol 32(2):145–155.  https://doi.org/10.1016/j.semnephrol.2012.02.001 CrossRefPubMedGoogle Scholar
  53. 53.
    Aird WC (2007) Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res 100(2):158–173.  https://doi.org/10.1161/01.RES.0000255691.76142.4a CrossRefPubMedGoogle Scholar
  54. 54.
    Aird WC (2012) Endothelial cell heterogeneity. Cold Spring Harb Perspect Med 2(1):a006429.  https://doi.org/10.1101/cshperspect.a006429 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Nolan DJ, Ginsberg M, Israely E, Palikuqi B, Poulos MG, James D, Ding BS, Schachterle W, Liu Y, Rosenwaks Z, Butler JM, Xiang J, Rafii A, Shido K, Rabbany SY, Elemento O, Rafii S (2013) Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration. Dev Cell 26(2):204–219.  https://doi.org/10.1016/j.devcel.2013.06.017 CrossRefPubMedGoogle Scholar
  56. 56.
    Brunskill EW, Potter SS (2010) Gene expression programs of mouse endothelial cells in kidney development and disease. PLoS ONE 5(8):e12034.  https://doi.org/10.1371/journal.pone.0012034 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Edward Daniel
    • 1
  • D. Berfin Azizoglu
    • 1
  • Anne R. Ryan
    • 1
  • Tezin A. Walji
    • 1
  • Christopher P. Chaney
    • 1
  • Gabrielle I. Sutton
    • 1
  • Thomas J. Carroll
    • 1
  • Denise K. Marciano
    • 2
  • Ondine Cleaver
    • 1
  1. 1.Department of Molecular Biology, Center for Regenerative Science and MedicineUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of Medicine, Division of NephrologyUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations