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

被引：83

作者：

Sun, Naidi ^{[1
]}

Ning, Bo ^{[1
]}

Hansson, Kenny M. ^{[2
]}

Bruce, Anthony C. ^{[1
]}

Seaman, Scott A. ^{[1
]}

Zhang, Chenchu ^{[1
]}

Rikard, Michaela ^{[1
]}

DeRosa, Christopher A. ^{[3
]}

Fraser, Cassandra L. ^{[3
]}

Wagberg, Maria ^{[2
]}

Fritsche-Danielson, Regina ^{[4
]}

Wikstrom, Johannes ^{[2
]}

Chien, Kenneth R. ^{[5
,6
]}

Lundahl, Anna ^{[7
]}

Holtta, Mikko ^{[8
]}

Carlsson, Leif G. ^{[2
]}

Peirce, Shayn M. ^{[1
]}

Hu, Song ^{[1
]}

机构：

[1] Univ Virginia, Dept Biomed Engn, Charlottesville, VA 22908 USA

[2] AstraZeneca, IMED Biotech Unit, Biosci Heart Failure Cardiovasc Renal & Metab, Gothenburg, Sweden

[3] Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA

[4] AstraZeneca, IMED Biotech Unit, Cardiovasc Renal & Metab, Gothenburg, Sweden

[5] Karolinska Inst, Integrated Cardiometab Ctr, SE-14152 Huddinge, Sweden

[6] Karolinska Inst, Dept Cell & Mol Biol & Med, SE-17177 Stockholm, Sweden

[7] AstraZeneca, IMED Biotech Unit, Dept Drug Metab & Pharmacokinet Cardiovasc Renal, Gothenburg, Sweden

[8] AstraZeneca, IMED Biotech Unit, Safety & ADME Translat Sci Drug Safety & Metab, Gothenburg, Sweden

来源：

SCIENTIFIC REPORTS | 2018年 / 8卷

关键词：

ENDOTHELIAL GROWTH-FACTOR; GENE-THERAPY; ANGIOGENESIS; BIOLOGY; CELLS;

D O I：

10.1038/s41598-018-35570-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11