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Sci Rep. 2018 Nov 30;8(1):17509. doi: 10.1038/s41598-018-35570-6.

Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing.

Author information

1
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, United States.
2
Bioscience Heart Failure Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
3
Department of Chemistry, University of Virginia, Charlottesville, Virginia, 22904, United States.
4
Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
5
Integrated Cardiometabolic Center, Karolinska Institute, SE-141 52, Huddinge, Sweden.
6
Department of Cell and Molecular Biology and Medicine, Karolinska Institute, SE-171 77, Stockholm, Sweden.
7
Department of Drug Metabolism and Pharmacokinetics Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
8
Safety & ADME Translational Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
9
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, United States. smp6p@virginia.edu.
10
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, United States. songhu@virginia.edu.

Abstract

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.

PMID:
30504800
PMCID:
PMC6269526
DOI:
10.1038/s41598-018-35570-6
[Indexed for MEDLINE]
Free PMC Article

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