| Autor: |
Sun N; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, United States., Ning B; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, United States., Hansson KM; Bioscience Heart Failure Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Bruce AC; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, United States., Seaman SA; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, United States., Zhang C; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, United States., Rikard M; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, United States., DeRosa CA; Department of Chemistry, University of Virginia, Charlottesville, Virginia, 22904, United States., Fraser CL; Department of Chemistry, University of Virginia, Charlottesville, Virginia, 22904, United States., Wågberg M; Bioscience Heart Failure Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Fritsche-Danielson R; Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Wikström J; Bioscience Heart Failure Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Chien KR; Integrated Cardiometabolic Center, Karolinska Institute, SE-141 52, Huddinge, Sweden.; Department of Cell and Molecular Biology and Medicine, Karolinska Institute, SE-171 77, Stockholm, Sweden., Lundahl A; Department of Drug Metabolism and Pharmacokinetics Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Hölttä M; Safety & ADME Translational Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Carlsson LG; Bioscience Heart Failure Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Peirce SM; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, United States. smp6p@virginia.edu., Hu S; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, United States. songhu@virginia.edu. |
| Abstrakt: |
Capable of mediating efficient transfection and protein production without eliciting innate immune responses, chemically modified mRNA holds great potential to produce paracrine factors at a physiologically beneficial level, in a spatiotemporally controlled manner, and with low toxicity. Although highly promising in cardiovascular medicine and wound healing, effects of this emerging therapeutic on the microvasculature and its bioactivity in disease settings remain poorly understood. Here, we longitudinally and comprehensively characterize microvascular responses to AZD8601, a modified mRNA encoding vascular endothelial growth factor A (VEGF-A), in vivo. Using multi-parametric photoacoustic microscopy, we show that intradermal injection of AZD8601 formulated in a biocompatible vehicle results in pronounced, sustained and dose-dependent vasodilation, blood flow upregulation, and neovessel formation, in striking contrast to those induced by recombinant human VEGF-A protein, a non-translatable variant of AZD8601, and citrate/saline vehicle. Moreover, we evaluate the bioactivity of AZD8601 in a mouse model of diabetic wound healing in vivo. Using a boron nanoparticle-based tissue oxygen sensor, we show that sequential dosing of AZD8601 improves vascularization and tissue oxygenation of the wound bed, leading to accelerated re-epithelialization during the early phase of diabetic wound healing. |
