Skip to main content

Advertisement

SpringerLink
Log in

2nd Window NIR Imaging of Radiation Injury Mitigation Provided by Reduced Notch-Dll4 Expression on Vasculature

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

Vascular endothelium plays a central role in the pathogenesis of acute and chronic radiation injuries, yet the mechanisms which promote sustained endothelial dysfunction and contribute to late responding organ failure are unclear. We employed 2nd window (> 1100 nm emission) Near-Infrared (NIR) imaging using indocyanine green (ICG) to track and define the role of the notch ligand Delta-like ligand 4 (Dll4) in mediating vascular injury in two late-responding radiosensitive organs: the lung and kidney.

Procedures

Consomic strains of female Salt Sensitive or SS (Dll4-high) and SS with 3rd chromosome inherited from Brown Norway, SS.BN3 (Dll4-low) rats at ages 11–12 weeks were used to demonstrate the impact of reduced Dll4 expression on long-term vascular integrity, renal function, and survival following high-dose 13 Gy partial body irradiation at 42- and 90 days post-radiation. 2nd window dynamic NIR fluorescence imaging with ICG was analyzed with physiology-based pharmacokinetic modeling and confirmed with assays of endothelial Dll4 expression to assess the role of endogenous Dll4 expression on radiation injury protection.

Results

We show that SS.BN3 (Dll4-low) rats are relatively protected from vascular permeability disruption compared to the SS (Dll4-high) strain. We further demonstrated that SS.BN3 (Dll4-low) rats have reduced radiation induced loss of CD31+ vascular endothelial cells, and increased Dll4 vascular expression is correlated with vascular dysfunction.

Conclusions

Together, these data suggest Dll4 plays a key role in pathogenesis of radiation-induced vascular injury to the lung and kidney.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

This study employed the established consomic rat models SS and SS.BN3. The publicly accessible and NIH supported Rat Genome Database (rgd.mcw.edu) catalogs and has tools to explore the genotype and phenotype information for the SS (Dll4-high) and SS.BN3 (Dll4-low) strains under strain records RRID: RGD_61499 and RRID: RGD_1358154, respectively. The PBPK analysis codes are available by request from the corresponding author.

References

  1. Kim A, Seong KM, Choi YY, Shim S, Park S, Lee SS (2020) Inhibition of EphA2 by dasatinib suppresses radiation-induced intestinal injury. Int J Mol Sci 21(23):9096. https://doi.org/10.3390/ijms21239096

  2. Wang J, Boerma M, Fu Q, Hauer-Jensen M (2007) Significance of endothelial dysfunction in the pathogenesis of early and delayed radiation enteropathy. World J Gastroenterol 13(22):3047–3055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Li XM, Hu Z, Jorgenson ML, Wingard JR, Slayton WB (2008) Bone marrow sinusoidal endothelial cells undergo nonapoptotic cell death and are replaced by proliferating sinusoidal cells in situ to maintain the vascular niche following lethal irradiation. Exp Hematol 36(9):1143–1156

    Article  CAS  PubMed  Google Scholar 

  4. Wang Y, Boerma M, Zhou D (2016) Ionizing radiation-induced endothelial cell senescence and cardiovascular diseases. Radiat Res 186(2):153–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cary L, Noutai D, Salber R, Fadiyimu O, Gross A, Almeida-Porada G, Kidane Y, Whitnall M (2019) Bone marrow endothelial cells influence function and phenotype of hematopoietic stem and progenitor cells after mixed neutron/gamma radiation. Int J Mol Sci 20(7):1795. https://doi.org/10.3390/ijms20071795

  6. Chen Q, Liu Y, Jeong HW, Stehling M, Dinh VV, Zhou B, Adams RH (2019) Apelin(+) endothelial niche cells control hematopoiesis and mediate vascular regeneration after myeloablative injury. Cell Stem Cell 25(6):768-783 e766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jang H, Lee J, Park S, Kim JS, Shim S, Lee SB, Han SH, Myung H, Kim H, Jang WS et al (2019) Baicalein mitigates radiation-induced enteritis by improving endothelial dysfunction. Front Pharmacol 10:892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li B, Bailey AS, Jiang S, Liu B, Goldman DC, Fleming WH (2010) Endothelial cells mediate the regeneration of hematopoietic stem cells. Stem Cell Res 4(1):17–24

    Article  PubMed  Google Scholar 

  9. Rotolo JA, Fong CS, Bodo S, Nagesh PK, Fuller J, Sharma T, Piersigilli A, Zhang Z, Fuks Z, Singh VK et al (2021) Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair. JCI Insight 6(8):e145380. https://doi.org/10.1172/jci.insight.145380

  10. Ghosh SN, Wu Q, Mader M, Fish BL, Moulder JE, Jacobs ER, Medhora M, Molthen RC (2009) Vascular injury after whole thoracic x-ray irradiation in the rat. Int J Radiat Oncol 74(1):192–199

    Article  CAS  Google Scholar 

  11. Robbins ME, Brunso-Bechtold JK, Peiffer AM, Tsien CI, Bailey JE, Marks LB (2012) Imaging radiation-induced normal tissue injury. Radiat Res 177(4):449–466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Unthank JL, Miller SJ, Quickery AK, Ferguson EL, Wang M, Sampson CH, Chua HL, DiStasi MR, Feng H, Fisher A (2015) Delayed effects of acute radiation exposure in a murine model of the h-ars: multiple-organ injury consequent to< 10 gy total body irradiation. Health Phys 109(5):511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Unthank JL, Ortiz M, Trivedi H, Pelus LM, Sampson CH, Sellamuthu R, Fisher A, Chua HL, Plett A, Orschell CM et al (2019) Cardiac and renal delayed effects of acute radiation exposure: organ differences in vasculopathy, inflammation, senescence and oxidative balance. Radiat Res 191(5):383–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Boerma M, Hauer-Jensen M (2010) Potential targets for intervention in radiation-induced heart disease. Curr Drug Targets 11(11):1405–1412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Baker JE, Fish BL, Su J, Haworth ST, Strande JL, Komorowski RA, Migrino RQ, Doppalapudi A, Harmann L, Allen Li X et al (2009) 10 gy total body irradiation increases risk of coronary sclerosis, degeneration of heart structure and function in a rat model. Int J Radiat Biol 85(12):1089–1100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Andrews RN, Bloomer EG, Olson JD, Hanbury DB, Dugan GO, Whitlow CT, Cline JM (2020) Non-human primates receiving high-dose total-body irradiation are at risk of developing cerebrovascular injury years postirradiation. Radiat Res 194(3):277–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mehrvar S, Mostaghimi S, Camara AK, Foomani F, Narayanan J, Fish B, Medhora M, Ranji M (2021) Three-dimensional vascular and metabolic imaging using inverted autofluorescence. J Biomed Opt 26(7):076002. https://doi.org/10.1117/1.jbo.26.7.076002

  18. Jagtap J, Audi S, Razeghi-Kondelaji MH, Fish BL, Hansen C, Narayan J, Gao F, Sharma G, Parchur AK, Banerjee A et al (2021) A rapid dynamic in vivo near-infrared fluorescence imaging assay to track lung vascular permeability after acute radiation injury. Am J Physiol Lung Cell Mol Physiol 320(3):L436–L450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD, Thurston GJN (2006) Blockade of dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444(7122):1032–1037

    Article  CAS  PubMed  Google Scholar 

  20. Gale NW, Dominguez MG, Noguera I, Pan L, Hughes V, Valenzuela DM, Murphy AJ, Adams NC, Lin HC, Holash J et al (2004) Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci U S A 101(45):15949–15954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Krebs LT, Shutter JR, Tanigaki K, Honjo T, Stark KL, Gridley T (2004) Haploinsufficient lethality and formation of arteriovenous malformations in notch pathway mutants. Genes Dev 18(20):2469–2473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, Bekman E, Costa L, Henrique D, Rossant J (2004) Dosage-sensitive requirement for mouse dll4 in artery development. Genes Dev 18(20):2474–2478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sharma G, Jagtap JM, Parchur AK, Gogineni VR, Ran S, Bergom C, White SB, Flister MJ, Joshi A (2020) Heritable modifiers of the tumor microenvironment influence nanoparticle uptake, distribution and response to photothermal therapy. Theranostics 10(12):5368–5383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Flister MJ, Tsaih SW, Stoddard A, Plasterer C, Jagtap J, Parchur AK, Sharma G, Prisco AR, Lemke A, Murphy D et al (2017) Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer. Breast Cancer Res Treat 165(1):53–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schlaak RA, Frei A, Schottstaedt AM, Tsaih S-W, Fish BL, Harmann L, Liu Q, Gasperetti T, Medhora M, North PE et al (2019) Mapping genetic modifiers of radiation-induced cardiotoxicity to rat chromosome 3. Am J Physiol Heart Circul Physiol 316(6):H1267–H1280

    Article  CAS  Google Scholar 

  26. Fish BL, MacVittie TJ, Szabo A, Moulder JE, Medhora M (2020) Wag/rijcmcr rat models for injuries to multiple organs by single high dose ionizing radiation: Similarities to nonhuman primates (nhp). Int J Radiat Biol 96(1):81–92

    Article  CAS  PubMed  Google Scholar 

  27. Medhora M, Gao F, Gasperetti T, Narayanan J, Khan AH, Jacobs ER, Fish BL (2019) Delayed effects of acute radiation exposure (deare) in juvenile and old rats: Mitigation by lisinopril. Health Phys 116(4):529–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang T, Chen Y, Wang B, Gao X, Wu M (2022) Recent progress in second near-infrared (nir-ii) fluorescence imaging in cancer. Biomolecules 12(8):1044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhu S, Hu Z, Tian R, Yung BC, Yang Q, Zhao S, Kiesewetter DO, Niu G, Sun H, Antaris AL et al (2018) Repurposing cyanine nir-i dyes accelerates clinical translation of near-infrared-ii (nir-ii) bioimaging. Advanced Materials 30(34):1802546

    Article  Google Scholar 

  30. Smith AM, Mancini MC, Nie S (2009) Bioimaging: second window for in vivo imaging. Nat Nanotechnol 4(11):710–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Starosolski Z, Bhavane R, Ghaghada KB, Vasudevan SA, Kaay A, Annapragada A (2017) Indocyanine green fluorescence in second near-infrared (nir-ii) window. PLoS ONE 12(11):e0187563

    Article  PubMed  PubMed Central  Google Scholar 

  32. Chi C, Ye J, Ding H, He D, Huang W, Zhang G-J, Tian J (2013) Use of indocyanine green for detecting the sentinel lymph node in breast cancer patients: from preclinical evaluation to clinical validation. PLoS ONE 8(12):e83927

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the arrive guidelines for reporting animal research. PLoS Biol 8(6):e1000412

    Article  PubMed  PubMed Central  Google Scholar 

  34. Flister MJ, Endres BT, Rudemiller N, Sarkis AB, Santarriaga S, Roy I, Lemke A, Geurts AM, Moreno C, Ran S et al (2014) Cxm: a new tool for mapping breast cancer risk in the tumor microenvironment. Can Res 74(22):6419–6429

    Article  CAS  Google Scholar 

  35. Fish BL, MacVittie TJ, Gao F, Narayanan J, Gasperetti T, Scholler D, Sheinin Y, Himburg HA, Hart B, Medhora M (2021) Rat models of partial-body irradiation with bone marrow-sparing (leg-out pbi) designed for fda approval of countermeasures for mitigation of acute and delayed injuries by radiation. Health Phys 121(4):419–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee HB, Blaufox MD (1985) Blood volume in the rat. J Nuclear Med: Official Publication, Soc Nuclear Med 26(1):72–76

    CAS  Google Scholar 

  37. Sharma GP, Fish BL, Frei AC, Narayanan J, Gasperetti T, Scholler D, Pierce L, Szalewski N, Blue N, Medhora M, Himburg HA (2022) Pharmacological ACE-inhibition mitigates radiation-induced pneumonitis by suppressing ACE-expressing lung myeloid cells. Int J Radiat Oncol Biol Phys 113(1):177–191. https://doi.org/10.1016/j.ijrobp.2022.01.023

  38. Sharma GP, Frei AC, Narayanan J, Gasperetti T, Veley D, Amjad A, Albano K, Fish BL, Himburg HA (2021) Brain-derived neurotrophic factor promotes immune reconstitution following radiation injury via activation of bone marrow mesenchymal stem cells. PLoS ONE 16(10):e0259042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fish BL, Gao F, Narayanan J, Bergom C, Jacobs ER, Cohen EP, Moulder JE, Orschell CM, Medhora M (2016) Combined hydration and antibiotics with lisinopril to mitigate acute and delayed high-dose radiation injuries to multiple organs. Health Phys 111(5):410–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bukowy JD, Dayton A, Cloutier D, Manis AD, Staruschenko A, Lombard JH, Solberg Woods LC, Beard DA, Cowley AW Jr (2018) Region-based convolutional neural nets for localization of glomeruli in trichrome-stained whole kidney sections. J Am Soc Nephrol 29(8):2081–2088

    Article  PubMed  PubMed Central  Google Scholar 

  41. Banerjee D, Barton SM, Grabham PW, Rumeld AL, Okochi S, Street C, Kadenhe-Chiweshe A, Boboila S, Yamashiro DJ, Connolly EP (2020) High-dose radiation increases notch1 in tumor vasculature. Int J Radiat Oncol Biol Phys 106(4):857–866

    Article  CAS  PubMed  Google Scholar 

  42. Scharpfenecker M, Kruse JJ, Sprong D, Russell NS, Ten Dijke P, Stewart FA (2009) Ionizing radiation shifts the pai-1/id-1 balance and activates notch signaling in endothelial cells. Int J Radiat Oncol Biol Phys 73(2):506–513

    Article  CAS  PubMed  Google Scholar 

  43. Yoneya S, Saito T, Komatsu Y, Koyama I, Takahashi K, Duvoll-Young J (1998) Binding properties of indocyanine green in human blood. Invest Ophthalmol Vis Sci 39(7):1286–1290

    CAS  PubMed  Google Scholar 

  44. Baradaran-Ghahfarokhi M (2012) Radiation-induced kidney injury. J Renal Inj Prev 1(2):49–50

    PubMed  PubMed Central  Google Scholar 

  45. Arichi N, Mitsui Y, Ogawa K, Nagami T, Nakamura S, Hiraoka T, Yasumoto H, Shiina H (2014) Intraoperative fluorescence vascular imaging using indocyanine green for assessment of transplanted kidney perfusion. Transpl Proc 46(2):342–345

    Article  CAS  Google Scholar 

  46. Mitsui Y, Shiina H, Arichi N, Hiraoka T, Inoue S, Sumura M, Honda S, Yasumoto H, Igawa M (2012) Indocyanine green (icg)-based fluorescence navigation system for discrimination of kidney cancer from normal parenchyma: Application during partial nephrectomy. Int Urol Nephrol 44(3):753–759

    Article  PubMed  Google Scholar 

  47. Trindade A, Djokovic D, Gigante J, Badenes M, Pedrosa AR, Fernandes AC, Lopes-da-Costa L, Krasnoperov V, Liu R, Gill PS et al (2012) Low-dosage inhibition of dll4 signaling promotes wound healing by inducing functional neo-angiogenesis. PLoS ONE 7(1):e29863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Djokovic D, Trindade A, Gigante J, Pinho M, Harris AL, Duarte A (2015) Incomplete dll4/notch signaling inhibition promotes functional angiogenesis supporting the growth of skin papillomas. BMC Cancer 15:608

    Article  PubMed  PubMed Central  Google Scholar 

  49. Poulos MG, Ramalingam P, Gutkin MC, Kleppe M, Ginsberg M, Crowley MJP, Elemento O, Levine RL, Rafii S, Kitajewski J et al (2016) Endothelial-specific inhibition of nf-kappab enhances functional haematopoiesis. Nat Commun 7:13829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Guo P, Poulos MG, Palikuqi B, Badwe CR, Lis R, Kunar B, Ding BS, Rabbany SY, Shido K, Butler JM et al (2017) Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression. J Clin Invest 127(12):4242–4256

    Article  PubMed  PubMed Central  Google Scholar 

  51. Poulos MG, Guo P, Kofler NM, Pinho S, Gutkin MC, Tikhonova A, Aifantis I, Frenette PS, Kitajewski J, Rafii S et al (2013) Endothelial jagged-1 is necessary for homeostatic and regenerative hematopoiesis. Cell Rep 4(5):1022–1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Del Gaudio F, Liu D, Lendahl U (2022) Notch signalling in healthy and diseased vasculature. Open Biol 12(4):220004

    Article  PubMed  PubMed Central  Google Scholar 

  53. Yang SS, Yu DY, Du YT, Wang L, Gu L, Zhang YY, Xiao M (2020) Inhibition of delta-like ligand 4 enhances the radiosensitivity and inhibits migration in cervical cancer via the reversion of epithelial-mesenchymal transition. Cancer Cell Int 20:344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by funding from NIH/NIAID U01AI133594 (PI H. Himburg), U01AI138331 (PI M. Medhora), NIH/NCI 2R01CA193343 (PI A. Joshi), MCW Department of Radiation Oncology, and the MCW Cancer Center.

Author information

Author notes

  1. Mir Hadi Razeghi Kondelaji and Guru Prasad Sharma contributed equally to the manuscript.

Authors and Affiliations

  1. Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI, USA

    Mir Hadi Razeghi Kondelaji, Shayan Shafiee, Christopher Hansen & Amit Joshi

  2. Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA

    Guru Prasad Sharma, Tracy Gasperetti, Anne Frei, Dana Veley, Jayashree Narayanan, Brian L. Fish, Abdul K. Parchur, Meetha Medhora & Heather A. Himburg

  3. Department of Radiology, Mayo Clinic, Rochester, MN, USA

    Jaidip Jagtap

  4. Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA

    El-Sayed H. Ibrahim

Authors
  1. Mir Hadi Razeghi Kondelaji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guru Prasad Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jaidip Jagtap
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shayan Shafiee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tracy Gasperetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anne Frei
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dana Veley
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jayashree Narayanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Brian L. Fish
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Abdul K. Parchur
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. El-Sayed H. Ibrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Meetha Medhora
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Heather A. Himburg
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Amit Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Heather A. Himburg or Amit Joshi.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file4 (DOCX 30 KB)

Supplementary file5 (JPG 3.47 MB)

Supplementary file6 (JPG 3.60 MB)

Supplementary file7 (JPG 1.25 MB)

Supplementary file8 (JPG 901 KB)

Supplementary file9 (JPG 1.99 MB)

Supplementary file10 (DOCX 13.3 KB)

Supplementary file11 (MP4 5.80 MB)

Supplementary file1 (MP4 5.42 MB)

Supplementary file2 (MP4 6.70 MB)

Supplementary file3 (MP4 2.50 MB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kondelaji, M.H.R., Sharma, G.P., Jagtap, J. et al. 2nd Window NIR Imaging of Radiation Injury Mitigation Provided by Reduced Notch-Dll4 Expression on Vasculature. Mol Imaging Biol 26, 124–137 (2024). https://doi.org/10.1007/s11307-023-01840-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-023-01840-7

Key words

Search

Navigation