Pre-Exposure Prophylaxis with Vasculotide Enhances Survival and Alleviates Hematopoietic and Gastrointestinal Injury Following Lethal Total Body Irradiation.

No US Food and Drug Administration (FDA)-approved prophylaxis is currently available for Acute Radiation Syndrome (ARS), which remains a significant threat to military and civilian populations. In this study, we investigated Vasculotide (VT), a Tie2 receptor agonist mimic, as a novel pre-exposure prophylaxis designed to stabilize the vascular endothelium, one of primary targets of radiation-induced damage. To evaluate its efficacy, female B6D2F1/J mice were exposed to 9.5 Gy total body irradiation (TBI), with VT administered subcutaneously at 12 and 2 h prior to exposure. Assessments included 30-day survival, biomarkers of vascular injury, proinflammatory cytokine/chemokine profiling, and evaluation of hematopoietic (H) and gastrointestinal (GI) recovery. Our findings demonstrate that VT significantly increased 30-day survival in a dose-dependent manner, achieving a 30% survival advantage at the 20 μg/kg dose. Furthermore, VT provided robust protection against radiation-induced vascular activation and injury, effectively alleviating damage to the bone marrow (BM) and GI tract. Taken together, these results identify VT as a promising prophylactic countermeasure for ARS. By targeting the Tie2 pathway to preserve vascular integrity, VT addresses a critical gap in medical countermeasures, offering a viable strategy to enhance survival and accelerate multi-organ recovery in radiological mass-casualty scenarios.