Loss of PPARγ in endothelial cells leads to impaired angiogenesis

J Cell Sci. 2016 Feb 15;129(4):693-705. doi: 10.1242/jcs.169011. Epub 2016 Jan 7.


Tie2-promoter-mediated loss of peroxisome proliferator-activated receptor gamma (PPARγ, also known as PPARG) in mice leads to osteopetrosis and pulmonary arterial hypertension. Vascular disease is associated with loss of PPARγ in pulmonary microvascular endothelial cells (PMVEC); we evaluated the role of PPARγ in PMVEC functions, such as angiogenesis and migration. The role of PPARγ in angiogenesis was evaluated in Tie2CrePPARγ(flox/flox) and wild-type mice, and in mouse and human PMVECs. RNA sequencing and bioinformatic approaches were utilized to reveal angiogenesis-associated targets for PPARγ. Tie2CrePPARγ(flox/flox) mice showed an impaired angiogenic capacity. Analysis of endothelial progenitor-like cells using bone marrow transplantation combined with evaluation of isolated PMVECs revealed that loss of PPARγ attenuates the migration and angiogenic capacity of mature PMVECs. PPARγ-deficient human PMVECs showed a similar migration defect in culture. Bioinformatic and experimental analyses newly revealed E2F1 as a target of PPARγ in the regulation of PMVEC migration. Disruption of the PPARγ-E2F1 axis was associated with a dysregulated Wnt pathway related to the GSK3B interacting protein (GSKIP). In conclusion, PPARγ plays an important role in sustaining angiogenic potential in mature PMVECs through E2F1-mediated gene regulation.

Keywords: Angiogenesis; E2F1; Endothelial cell; GSKIP; Osteopetrosis; PPARγ; Pulmonary hypertension; Wnt signaling.

Publication types

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

MeSH terms

  • Animals
  • Bone Marrow Transplantation
  • Cell Movement
  • Cells, Cultured
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism
  • Endothelial Cells / physiology*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / physiology
  • Gene Expression
  • Humans
  • Lung / blood supply
  • Mice
  • Mice, Transgenic
  • Neovascularization, Physiologic
  • PPAR gamma / genetics*
  • PPAR gamma / metabolism
  • Transcriptional Activation
  • Wnt Signaling Pathway
  • beta Catenin / metabolism


  • CTNNB1 protein, mouse
  • E2F1 Transcription Factor
  • E2f1 protein, mouse
  • PPAR gamma
  • beta Catenin