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2nd Window NIR Imaging of Radiation Injury Mitigation Provided by Reduced Notch-Dll4 Expression on Vasculature. Mol Imaging Biol 2024 Feb;26(1):124-137

Date

08/02/2023

Pubmed ID

37530966

DOI

10.1007/s11307-023-01840-7

Scopus ID

2-s2.0-85166543488 (requires institutional sign-in at Scopus site)   1 Citation

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.

Author List

Kondelaji MHR, Sharma GP, Jagtap J, Shafiee S, Hansen C, Gasperetti T, Frei A, Veley D, Narayanan J, Fish BL, Parchur AK, Ibrahim EH, Medhora M, Himburg HA, Joshi A

Authors

Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin
Amit Joshi PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
Guru Prasad Sharma PhD Research Scientist I in the Radiation Oncology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Endothelial Cells
Female
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Radiation Injuries
Rats
Vascular System Injuries