VEGF receptor 2 (KDR) protects airways from mucus metaplasia through a Sox9-dependent pathway

Dev Cell. 2021 Jun 7;56(11):1646-1660.e5. doi: 10.1016/j.devcel.2021.04.027. Epub 2021 May 18.


Mucus-secreting goblet cells are the dominant cell type in pulmonary diseases, e.g., asthma and cystic fibrosis (CF), leading to pathologic mucus metaplasia and airway obstruction. Cytokines including IL-13 are the major players in the transdifferentiation of club cells into goblet cells. Unexpectedly, we have uncovered a previously undescribed pathway promoting mucous metaplasia that involves VEGFa and its receptor KDR. Single-cell RNA sequencing analysis coupled with genetic mouse modeling demonstrates that loss of epithelial VEGFa, KDR, or MEK/ERK kinase promotes excessive club-to-goblet transdifferentiation during development and regeneration. Sox9 is required for goblet cell differentiation following Kdr inhibition in both mouse and human club cells. Significantly, airway mucous metaplasia in asthmatic and CF patients is also associated with reduced KDR signaling and increased SOX9 expression. Together, these findings reveal an unexpected role for VEGFa/KDR signaling in the defense against mucous metaplasia, offering a potential therapeutic target for this common airway pathology.

Keywords: KDR; MAPK; Sox9; VEGFR2; VEGFa; airway; club cell; goblet cell; mucous cell; regeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Obstruction / genetics*
  • Airway Obstruction / metabolism
  • Airway Obstruction / pathology
  • Animals
  • Cell Transdifferentiation / genetics
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Goblet Cells / metabolism
  • Goblet Cells / pathology
  • Humans
  • Interleukin-13 / genetics
  • MAP Kinase Signaling System / genetics
  • Metaplasia / genetics*
  • Metaplasia / pathology
  • Mice
  • Mucus / metabolism
  • SOX9 Transcription Factor / genetics*
  • Single-Cell Analysis
  • Vascular Endothelial Growth Factor A / genetics*
  • Vascular Endothelial Growth Factor Receptor-2 / genetics*


  • Interleukin-13
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2