Modeling Cardiovascular Risks of E-Cigarettes With Human-Induced Pluripotent Stem Cell–Derived Endothelial Cells

Won Hee Lee, Sang Ging Ong, Yang Zhou, Lei Tian, Hye Ryeong Bae, Natalie Baker, Adam Whitlatch, Leila Mohammadi, Hongchao Guo, Kari C. Nadeau, Matthew L. Springer, Suzaynn F. Schick, Aruni Bhatnagar, Joseph C. Wu

Research output: Contribution to journalArticlepeer-review

96 Scopus citations


Background: Electronic cigarettes (e-cigarettes) have experienced a tremendous increase in use. Unlike cigarette smoking, the effects of e-cigarettes and their constituents on mediating vascular health remain understudied. However, given their increasing popularity, it is imperative to evaluate the health risks of e-cigarettes, including the effects of their ingredients, especially nicotine and flavorings. Objectives: The purpose of this study was to investigate the effects of flavored e-cigarette liquids (e-liquids) and serum isolated from e-cigarette users on endothelial health and endothelial cell–dependent macrophage activation. Methods: Human-induced pluripotent stem cell–derived endothelial cells (iPSC-ECs) and a high-throughput screening approach were used to assess endothelial integrity following exposure to 6 different e-liquids with varying nicotine concentrations and to serum from e-cigarette users. Results: The cytotoxicity of the e-liquids varied considerably, with the cinnamon-flavored product being most potent and leading to significantly decreased cell viability, increased reactive oxygen species (ROS) levels, caspase 3/7 activity, and low-density lipoprotein uptake, activation of oxidative stress-related pathway, and impaired tube formation and migration, confirming endothelial dysfunction. Upon exposure of ECs to e-liquid, conditioned media induced macrophage polarization into a pro-inflammatory state, eliciting the production of interleukin-1β and -6, leading to increased ROS. After exposure of human iPSC-ECs to serum of e-cigarette users, increased ROS linked to endothelial dysfunction was observed, as indicated by impaired pro-angiogenic properties. There was also an observed increase in inflammatory cytokine expression in the serum of e-cigarette users. Conclusions: Acute exposure to flavored e-liquids or e-cigarette use exacerbates endothelial dysfunction, which often precedes cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)2722-2737
Number of pages16
JournalJournal of the American College of Cardiology
Issue number21
StatePublished - Jun 4 2019
Externally publishedYes


  • e-cigarette aerosol
  • e-liquid flavoring
  • endothelial dysfunction
  • iPSC-ECs

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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