Vasculotide, an Angiopoietin-1 mimetic, reduces acute skin ionizing radiation damage in a preclinical mouse model

Abstract

Background Most cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Acute skin damage from cancer radiotherapy diminishes patients’ quality of life, yet effective biological interventions for this damage are lacking. Protecting microvascular endothelial cells from irradiation-induced perturbations is emerging as a targeted damage-reduction strategy. Since Angiopoetin-1 signaling through the Tie2 receptor on endothelial cells opposes microvascular perturbations in other disease contexts, we used a preclinical Angiopoietin-1 mimic called Vasculotide to investigate its effect on skin radiation toxicity using a preclinical model. Methods Athymic mice were treated intraperitoneally with saline or Vasculotide and their flank skin was irradiated with a single large dose of ionizing radiation. Acute cutaneous damage and wound healing were evaluated by clinical skin grading, histology and immunostaining. Diffuse reflectance optical spectroscopy, myeloperoxidase-dependent bioluminescence imaging of neutrophils and a serum cytokine array were used to assess inflammation. Microvascular endothelial cell response to radiation was tested with in vitro clonogenic and Matrigel tubule formation assays. Tumour xenograft growth delay experiments were also performed. Appreciable differences between treatment groups were assessed mainly using parametric and non-parametric statistical tests comparing areas under curves, followed by post-hoc comparisons. Results In vivo, different schedules of Vasculotide treatment reduced the size of the irradiation-induced wound. Although skin damage scores remained similar on individual days, Vasculotide administered post irradiation resulted in less skin damage overall. Vasculotide alleviated irradiation-induced inflammation in the form of reduced levels of oxygenated hemoglobin, myeloperoxidase bioluminescence and chemokine MIP-2. Surprisingly, Vasculotide-treated animals also had higher microvascular endothelial cell density in wound granulation tissue. In vitro, Vasculotide enhanced the survival and function of irradiated endothelial cells. Conclusions Vasculotide administration reduces acute skin radiation damage in mice, and may do so by affecting several biological processes. This radiation protection approach may have clinical impact for cancer radiotherapy patients by reducing the severity of their acute skin radiation damage.