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Linalool inhibits the angiogenic activity of endothelial cells by downregulating intracellular ATP levels and activating TRPM8.

Authors
  • Becker, Vivien1
  • Hui, Xin2
  • Nalbach, Lisa1
  • Ampofo, Emmanuel1
  • Lipp, Peter2
  • Menger, Michael D1
  • Laschke, Matthias W1
  • Gu, Yuan3
  • 1 Institute for Clinical & Experimental Surgery, Saarland University, 66421, Homburg, Saarland, Germany. , (Germany)
  • 2 Molecular Cell Biology, Research Center for Molecular Imaging and Screening, Medical Faculty, Saarland University, 66421, Homburg, Saarland, Germany. , (Germany)
  • 3 Institute for Clinical & Experimental Surgery, Saarland University, 66421, Homburg, Saarland, Germany. [email protected] , (Germany)
Type
Published Article
Journal
Angiogenesis
Publisher
Springer-Verlag
Publication Date
Mar 02, 2021
Identifiers
DOI: 10.1007/s10456-021-09772-y
PMID: 33655414
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Angiogenesis crucially contributes to various diseases, such as cancer and diabetic retinopathy. Hence, anti-angiogenic therapy is considered as a powerful strategy against these diseases. Previous studies reported that the acyclic monoterpene linalool exhibits anticancer, anti-inflammatory and anti-oxidative activity. However, the effects of linalool on angiogenesis still remain elusive. Therefore, we investigated the action of (3R)-(-)-linalool, a main enantiomer of linalool, on the angiogenic activity of human dermal microvascular endothelial cells (HDMECs) by a panel of angiogenesis assays. Non-cytotoxic doses of linalool significantly inhibited HDMEC proliferation, migration, tube formation and spheroid sprouting. Linalool also suppressed the vascular sprouting from rat aortic rings. In addition, Matrigel plugs containing linalool exhibited a significantly reduced microvessel density 7 days after implantation into BALB/c mice. Mechanistic analyses revealed that linalool promotes the phosphorylation of extracellular signal-regulated kinase (ERK), downregulates the intracellular level of adenosine triphosphate (ATP) and activates the transient receptor potential cation channel subfamily M (melastatin) member (TRPM)8 in HDMECs. Inhibition of ERK signaling, supplementation of ATP and blockade of TRPM8 significantly counteracted linalool-suppressed HDMEC spheroid sprouting. Moreover, ATP supplementation completely reversed linalool-induced ERK phosphorylation. In addition, linalool-induced ERK phosphorylation inhibited the expression of bone morphogenetic protein (BMP)-2 and linalool-induced TRPM8 activation caused the inhibition of β1 integrin/focal adhesion kinase (FAK) signaling. These findings indicate an anti-angiogenic effect of linalool, which is mediated by downregulating intracellular ATP levels and activating TRPM8.

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