High-throughput identification of small molecules that affect human embryonic vascular development

Research output: Contribution to journalArticle

Abstract

Birth defects, which are in part caused by exposure to environmental chemicals and pharmaceutical drugs, affect 1 in every 33 babies born in the United States each year. The current standard to screen drugs that affect embryonic development is based on prenatal animal testing; however, this approach yields low-throughput and limited mechanistic information regarding the biological pathways and potential adverse consequences in humans. To develop a screening platform for molecules that affect human embryonic development based on endothelial cells (ECs) derived from human pluripotent stem cells, we differentiated human pluripotent stem cells into embryonic ECs and induced their maturation under arterial flow conditions. These cells were then used to screen compounds that specifically affect embryonic vasculature. Using this platform, we have identified two compounds that have higher inhibitory effect in embryonic than postnatal ECs. One of them was fluphenazine (an antipsychotic), which inhibits calmodulin kinase II. The other compound was pyrrolopyrimidine (an antiinflammatory agent), which inhibits vascular endothelial growth factor receptor 2 (VEGFR2), decreases EC viability, induces an inflammatory response, and disrupts preformed vascular networks. The vascular effect of the pyrrolopyrimidine was further validated in prenatal vs. adult mouse ECs and in embryonic and adult zebrafish. We developed a platform based on human pluripotent stem cell-derived ECs for drug screening, which may open new avenues of research for the study and modulation of embryonic vasculature.

Details

Authors
  • Helena Vazão
  • Susana Rosa
  • Tânia Barata
  • Ricardo Costa
  • Patrícia R Pitrez
  • Inês Honório
  • Margreet R de Vries
  • Dimitri Papatsenko
  • Rui Benedito
  • Daniel Saris
  • Ali Khademhosseini
  • Paul H A Quax
  • Carlos F Pereira
  • Nadia Mercader
  • Hugo Fernandes
  • Lino Ferreira
External organisations
  • University of Coimbra
  • University of Twente
  • Centro Nacional de Investigaciones Cardiovasculares Carlos III
  • Leiden University Medical Centre
  • Icahn School of Medicine at Mount Sinai
  • King Abdulaziz University
  • University of Bern
Research areas and keywords

Keywords

  • Journal Article
Original languageEnglish
Pages (from-to)E3022-E3031
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number15
Publication statusPublished - 2017 Apr 11
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes