Angelica Dahurica ethanolic extract improves impaired wound healing by activating angiogenesis in diabetes

PLoS One. 2017 May 24;12(5):e0177862. doi: 10.1371/journal.pone.0177862. eCollection 2017.

Abstract

Abnormal angiogenesis plays an important role in impaired wound healing and development of chronic wounds in diabetes mellitus. Angelica dahurica radix is a common traditional Chinese medicine with wide spectrum medicinal effects. In this study, we analyzed the potential roles of Angelica dahurica ethanolic extract (ADEE) in correcting impaired angiogenesis and delayed wound healing in diabetes by using streptozotocin-induced diabetic rats. ADEE treatment accelerated diabetic wound healing through inducing angiogenesis and granulation tissue formation. The angiogenic property of ADEE was subsequently verified ex vivo using aortic ring assays. Furthermore, we investigated the in vitro angiogenic activity of ADEE and its underlying mechanisms using human umbilical vein endothelial cells. ADEE treatment induced HUVECs proliferation, migration, and tube formation, which are typical phenomena of angiogenesis, in dose-dependent manners. These effects were associated with activation of angiogenic signal modulators, including extracellular signal-regulated kinase 1/2 (ERK1/2), Akt, endothelial nitric oxide synthase (eNOS) as well as increased NO production, and independent of affecting VEGF expression. ADEE-induced angiogenic events were inhibited by the MEK inhibitor PD98059, the PI3K inhibitor Wortmannin, and the eNOS inhibitor L-NAME. Our findings highlight an angiogenic role of ADEE and its ability to protect against impaired wound healing, which may be developed as a promising therapy for impaired angiogenesis and delayed wound healing in diabetes.

MeSH terms

  • Androstadienes / pharmacology
  • Angelica / metabolism*
  • Animals
  • Aorta / metabolism
  • Cell Line
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Diabetes Mellitus, Experimental / pathology*
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flavonoids / pharmacology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Medicine, Chinese Traditional
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Neovascularization, Physiologic / drug effects*
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Nitric Oxide Synthase Type III / metabolism
  • Plant Extracts / therapeutic use*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Streptozocin
  • Wortmannin
  • Wound Healing / drug effects*

Substances

  • Androstadienes
  • Flavonoids
  • Plant Extracts
  • Nitric Oxide
  • Streptozocin
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • NG-Nitroarginine Methyl Ester
  • Wortmannin

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81273916) and Youth Incubation Fund of Tianjin Medical University General Hospital (No. ZYYFY2016019).