{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T23:53:48Z","timestamp":1785455628973,"version":"3.56.0"},"reference-count":55,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T00:00:00Z","timestamp":1732147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AFRRI Intramural","award":["HU00012420032 (PAT-74-12936)"],"award-info":[{"award-number":["HU00012420032 (PAT-74-12936)"]}]},{"name":"AFRRI Intramural","award":["HU000124F0029 (AFR-B2-2650)"],"award-info":[{"award-number":["HU000124F0029 (AFR-B2-2650)"]}]},{"name":"NIH\/NIAID-USUHS\/AFRRI IAA","award":["HU00012420032 (PAT-74-12936)"],"award-info":[{"award-number":["HU00012420032 (PAT-74-12936)"]}]},{"name":"NIH\/NIAID-USUHS\/AFRRI IAA","award":["HU000124F0029 (AFR-B2-2650)"],"award-info":[{"award-number":["HU000124F0029 (AFR-B2-2650)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Currently, there are no U.S. Food and Drug Administration (FDA)-approved medical countermeasures (MCMs) for radiation combined injury (RCI), partially due to limited understanding of its mechanisms. Our previous research suggests that endothelial dysfunction may contribute to a poor prognosis of RCI. In this study, we demonstrated an increased risk of mortality, body weight loss, and delayed skin wound healing in RCI mice compared to mice with skin wounds alone or radiation injury (RI) 30 days post-insult. Furthermore, we evaluated biomarkers of endothelial dysfunction, inflammation, and impaired wound healing in mice at early time points after RCI. Mice were exposed to 9.0 Gy total-body irradiation (TBI) followed by skin wound. Samples were collected on days 3, 7, and 14 post-TBI. Endothelial dysfunction markers were measured by ELISA, and skin wound healing was assessed histologically. Our results show that endothelial damage and inflammation are more severe and persistent in the RCI compared to the wound-alone group. Additionally, RCI impairs granulation tissue formation, reduces myofibroblast presence, and delays collagen deposition, correlating with more severe endothelial damage. TGF signaling may play a key role in this impaired healing. These findings suggest that targeting the endothelial dysfunction and TGF-\u03b2 pathways may provide potential therapeutic strategies for improving delayed wound healing in RCI, which could subsequently influence outcomes such as survival after RCI.<\/jats:p>","DOI":"10.3390\/ijms252312498","type":"journal-article","created":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T04:46:11Z","timestamp":1732164371000},"page":"12498","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Endothelial Dysfunction and Impaired Wound Healing Following Radiation Combined Skin Wound Injury"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4700-989X","authenticated-orcid":false,"given":"Li","family":"Wang","sequence":"first","affiliation":[{"name":"Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"},{"name":"Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"},{"name":"Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Lin","sequence":"additional","affiliation":[{"name":"Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"},{"name":"Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhai","sequence":"additional","affiliation":[{"name":"Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"},{"name":"Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Hull","sequence":"additional","affiliation":[{"name":"Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"},{"name":"Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6408-8601","authenticated-orcid":false,"given":"Wanchang","family":"Cui","sequence":"additional","affiliation":[{"name":"Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"},{"name":"Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"},{"name":"Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mang","family":"Xiao","sequence":"additional","affiliation":[{"name":"Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wang, L., Lin, B., Zhai, M., Cui, W., Hull, L., Zizzo, A., Li, X., Kiang, J.G., and Xiao, M. (2022). Deteriorative Effects of Radiation Injury Combined with Skin Wounding in a Mouse Model. Toxics, 10.","DOI":"10.3390\/toxics10120785"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1667\/RADE-20-00151.1","article-title":"PEG-G-CSF and L-Citrulline Combination Therapy for Mitigating Skin Wound Combined Radiation Injury in a Mouse Model","volume":"196","author":"Wang","year":"2021","journal-title":"Radiat. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1097\/HP.0b013e3181a6ee32","article-title":"Radiation combined injury: Overview of NIAID research","volume":"98","author":"DiCarlo","year":"2010","journal-title":"Health Phys."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1080\/09553002.2023.2188933","article-title":"Combined radiation injury and its impacts on radiation countermeasures and biodosimetry","volume":"99","author":"Kiang","year":"2023","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1007\/s10029-006-0150-y","article-title":"Radiation responses in skin and connective tissues: Effect on wound healing and surgical outcome","volume":"10","author":"Wang","year":"2006","journal-title":"Hernia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1097\/01.HP.0000348466.09978.77","article-title":"Combined injury: Factors with potential to impact radiation dose assessments","volume":"98","author":"Ledney","year":"2010","journal-title":"Health Phys."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1667\/RR1892.1","article-title":"Wound trauma increases radiation-induced mortality by activation of iNOS pathway and elevation of cytokine concentrations and bacterial infection","volume":"173","author":"Kiang","year":"2010","journal-title":"Radiat. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Xiao, M., Li, X., Wang, L., Lin, B., Zhai, M., Hull, L., Zizzo, A., Cui, W., and Kiang, J.G. (2023). Skin Wound following Irradiation Aggravates Radiation-Induced Brain Injury in a Mouse Model. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310701"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1097\/HP.0000000000000108","article-title":"Ciprofloxacin increases survival after ionizing irradiation combined injury: Gamma-H2AX formation, cytokine\/chemokine, and red blood cells","volume":"106","author":"Kiang","year":"2014","journal-title":"Health Phys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1667\/RR14647.1","article-title":"Combined Therapy of Pegylated G-CSF and Alxn4100TPO Improves Survival and Mitigates Acute Radiation Syndrome after Whole-Body Ionizing Irradiation Alone and Followed by Wound Trauma","volume":"188","author":"Kiang","year":"2017","journal-title":"Radiat. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13578-020-00425-z","article-title":"Ghrelin, a novel therapy, corrects cytokine and NF-kappaB-AKT-MAPK network and mitigates intestinal injury induced by combined radiation and skin-wound trauma","volume":"10","author":"Kiang","year":"2020","journal-title":"Cell Biosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e100862","DOI":"10.15252\/embj.2018100862","article-title":"Putting a strain on diversity","volume":"37","author":"Selman","year":"2018","journal-title":"EMBO J."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sloin, H.E., Bikovski, L., Levi, A., Amber-Vitos, O., Katz, T., Spivak, L., Someck, S., Gattegno, R., Sivroni, S., and Sjulson, L. (2022). Hybrid Offspring of C57BL\/6J Mice Exhibit Improved Properties for Neurobehavioral Research. eNeuro, 9.","DOI":"10.1101\/2022.05.03.490527"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.radonc.2021.02.007","article-title":"Mechanisms of radiation-induced endothelium damage: Emerging models and technologies","volume":"158","author":"Wijerathne","year":"2021","journal-title":"Radiother. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41569-022-00739-0","article-title":"Mechanisms and consequences of endothelial cell senescence","volume":"20","author":"Bloom","year":"2023","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_16","unstructured":"Alhajj, M., and Goyal, A. (2024). Physiology, Granulation Tissue. StatPearls, StatPearls Publishing."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.addr.2018.09.010","article-title":"Therapeutic strategies for enhancing angiogenesis in wound healing","volume":"146","author":"Veith","year":"2019","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_18","first-page":"183","article-title":"Endothelial dysfunction: Cardiovascular risk factors, therapy, and outcome","volume":"1","author":"Hadi","year":"2005","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.ccc.2019.12.009","article-title":"Nitric Oxide and Endothelial Dysfunction","volume":"36","author":"Cyr","year":"2020","journal-title":"Crit. Care Clin."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e12221","DOI":"10.1002\/pul2.12221","article-title":"Impact of l-citrulline on nitric oxide signaling and arginase activity in hypoxic human pulmonary artery endothelial cells","volume":"13","author":"Douglass","year":"2023","journal-title":"Pulm. Circ."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pacinella, G., Ciaccio, A.M., and Tuttolomondo, A. (2022). Endothelial Dysfunction and Chronic Inflammation: The Cornerstones of Vascular Alterations in Age-Related Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415722"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13578-019-0286-y","article-title":"Radiation: A poly-traumatic hit leading to multi-organ injury","volume":"9","author":"Kiang","year":"2019","journal-title":"Cell Biosci."},{"key":"ref_23","unstructured":"Gorbunov, N.V. (2021). Chapter Two\u2014Effects of radiation on endothelial barrier and vascular integrity. Tissue Barriers in Disease, Injury and Regeneration, Elsevier BV."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1007\/s00018-018-2956-z","article-title":"Pathological effects of ionizing radiation: Endothelial activation and dysfunction","volume":"76","author":"Baselet","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13014-014-0266-7","article-title":"Endothelial perturbations and therapeutic strategies in normal tissue radiation damage","volume":"9","author":"Korpela","year":"2014","journal-title":"Radiat. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sharma, G.P., and Himburg, H.A. (2022). Organ-Specific Endothelial Dysfunction Following Total Body Irradiation Exposure. Toxics, 10.","DOI":"10.3390\/toxics10120747"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.jacbts.2018.01.014","article-title":"Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms","volume":"3","author":"Venkatesulu","year":"2018","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.3748\/wjg.v13.i22.3047","article-title":"Significance of endothelial dysfunction in the pathogenesis of early and delayed radiation enteropathy","volume":"13","author":"Wang","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.mehy.2016.09.024","article-title":"Endothelial dysfunction may play a key role in keloid and hypertrophic scar pathogenesis\u2014Keloids and hypertrophic scars may be vascular disorders","volume":"96","author":"Ogawa","year":"2016","journal-title":"Med. Hypotheses"},{"key":"ref_30","first-page":"87","article-title":"Vascular inflammation and endothelial dysfunction in fracture healing","volume":"41","author":"Blum","year":"2012","journal-title":"Am. J. Orthop."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1097\/01.ta.0000195979.25659.fe","article-title":"Impact of severity of local soft-tissue trauma on long-term manifestation of microcirculatory and microlymphatic dysfunctions","volume":"61","author":"Amon","year":"2006","journal-title":"J. Trauma"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"F933","DOI":"10.1152\/ajprenal.00122.2001","article-title":"Role of connective tissue growth factor in fibronectin expression and tubulointerstitial fibrosis","volume":"282","author":"Yokoi","year":"2002","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sun, H.J., Wu, Z.Y., Nie, X.W., and Bian, J.S. (2019). Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01568"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3082","DOI":"10.1016\/j.jid.2022.04.018","article-title":"Timely Wound Healing Is Dependent on Endothelial but Not on Hair Follicle Stem Cell Toll-Like Receptor 2 Signaling","volume":"142","author":"Xiong","year":"2022","journal-title":"J. Investig. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.tcb.2005.09.002","article-title":"Inflammatory cells during wound repair: The good, the bad and the ugly","volume":"15","author":"Martin","year":"2005","journal-title":"Trends Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"67","DOI":"10.5858\/2001-125-0067-ROLAEC","article-title":"Role of leukocytes and endothelial cells in the development of angiogenesis in inflammation and wound healing","volume":"125","author":"Lingen","year":"2001","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"299","DOI":"10.12968\/jowc.2000.9.6.25994","article-title":"The physiology of wound healing","volume":"9","author":"Flanagan","year":"2000","journal-title":"J. Wound Care"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1089\/wound.2013.0517","article-title":"Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair","volume":"3","author":"Johnson","year":"2014","journal-title":"Adv. Wound Care (New Rochelle)"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1016\/j.apsb.2022.01.007","article-title":"Multifunctional regulatory protein connective tissue growth factor (CTGF): A potential therapeutic target for diverse diseases","volume":"12","author":"Fu","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Rebolledo, D.L., Lipson, K.E., and Brandan, E. (2021). Driving fibrosis in neuromuscular diseases: Role and regulation of Connective tissue growth factor (CCN2\/CTGF). Matrix Biol. Plus, 11.","DOI":"10.1016\/j.mbplus.2021.100059"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Tsai, C.C., Wu, S.B., Kau, H.C., and Wei, Y.H. (2018). Essential role of connective tissue growth factor (CTGF) in transforming growth factor-beta1 (TGF-beta1)-induced myofibroblast transdifferentiation from Graves\u2019 orbital fibroblasts. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-25370-3"},{"key":"ref_42","first-page":"75","article-title":"The role of myofibroblasts in wound healing, contraction and its clinical implications in cleft palate repair","volume":"7","author":"Chitturi","year":"2015","journal-title":"J. Int. Oral Health"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/cr.2008.326","article-title":"TGF-beta signaling in vascular biology and dysfunction","volume":"19","author":"Goumans","year":"2009","journal-title":"Cell Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1093\/jb\/mvq043","article-title":"Cellular and molecular basis for the regulation of inflammation by TGF-beta","volume":"147","author":"Yoshimura","year":"2010","journal-title":"J. Biochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.matbio.2015.05.006","article-title":"The extracellular matrix and transforming growth factor-beta1: Tale of a strained relationship","volume":"47","author":"Hinz","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41392-024-01764-w","article-title":"TGF-beta signaling in health, disease, and therapeutics","volume":"9","author":"Deng","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Liarte, S., Bernabe-Garcia, A., and Nicolas, F.J. (2020). Role of TGF-beta in Skin Chronic Wounds: A Keratinocyte Perspective. Cells, 9.","DOI":"10.3390\/cells9020306"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1089\/wound.2013.0429","article-title":"Dynamics of Transforming Growth Factor Beta Signaling in Wound Healing and Scarring","volume":"2","author":"Finnson","year":"2013","journal-title":"Adv. Wound Care (New Rochelle)"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Akwii, R.G., Sajib, M.S., Zahra, F.T., and Mikelis, C.M. (2019). Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology. Cells, 8.","DOI":"10.3390\/cells8050471"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Sim, S.L., Kumari, S., Kaur, S., and Khosrotehrani, K. (2022). Macrophages in Skin Wounds: Functions and Therapeutic Potential. Biomolecules, 12.","DOI":"10.3390\/biom12111659"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ridiandries, A., Tan, J.T.M., and Bursill, C.A. (2018). The Role of Chemokines in Wound Healing. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103217"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1080\/09553002.2017.1356941","article-title":"Whole body proton irradiation causes acute damage to bone marrow hematopoietic progenitor and stem cells in mice","volume":"93","author":"Chang","year":"2017","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"431","DOI":"10.2307\/3578885","article-title":"The effect of local and systemic irradiation on impairment of wound healing in mice","volume":"135","author":"Vegesna","year":"1993","journal-title":"Radiat. Res."},{"key":"ref_54","first-page":"445","article-title":"Non-invasive imaging of microcirculation: A technology review","volume":"7","author":"Eriksson","year":"2014","journal-title":"Med. Devices"},{"key":"ref_55","first-page":"19","article-title":"Development of a Multi-Organ Radiation Injury Model with Precise Dosimetry with Focus on GI-ARS","volume":"201","author":"Kumar","year":"2024","journal-title":"Radiat. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12498\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:36:27Z","timestamp":1760114187000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12498"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,21]]},"references-count":55,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252312498"],"URL":"https:\/\/doi.org\/10.3390\/ijms252312498","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,21]]}}}