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Research Article
Loss of PPARγ in endothelial cells leads to impaired angiogenesis
Sanna Vattulainen-Collanus, Oyediran Akinrinade, Molong Li, Minna Koskenvuo, Caiyun Grace Li, Shailaja P. Rao, Vinicio de Jesus Perez, Ke Yuan, Hirofumi Sawada, Juha W. Koskenvuo, Cristina Alvira, Marlene Rabinovitch, Tero-Pekka Alastalo
Journal of Cell Science 2016 129: 693-705; doi: 10.1242/jcs.169011
Sanna Vattulainen-Collanus
1Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland
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Oyediran Akinrinade
1Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland
2Institute of Biomedicine, University of Helsinki, Helsinki 00290, Finland
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Molong Li
3The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland
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Minna Koskenvuo
5Children's Hospital Helsinki, Division of Hematology-Oncology and Stem Cell Transplantation, University of Helsinki and Helsinki University Central Hospital, 00290 Helsinki, Finland
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Caiyun Grace Li
6Department of Pediatrics, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute Stanford University, Stanford, CA 94305, USA
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Shailaja P. Rao
6Department of Pediatrics, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute Stanford University, Stanford, CA 94305, USA
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Vinicio de Jesus Perez
7Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA
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Ke Yuan
7Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA
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Hirofumi Sawada
6Department of Pediatrics, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute Stanford University, Stanford, CA 94305, USA
8Department of Pediatrics, Mie University Graduate School of Medicine, Mie 5148507, Japan
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Juha W. Koskenvuo
4Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland
9Department of Clinical Physiology and Nuclear Medicine, HUS Medical Imaging Center, Helsinki University Central Hospital and University of Helsinki, 00290 Helsinki, Finland
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Cristina Alvira
6Department of Pediatrics, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute Stanford University, Stanford, CA 94305, USA
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Marlene Rabinovitch
6Department of Pediatrics, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute Stanford University, Stanford, CA 94305, USA
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Tero-Pekka Alastalo
1Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland
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  • For correspondence: tero-pekka.alastalo@helsinki.fi
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ABSTRACT

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 Tie2CrePPARγflox/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. Tie2CrePPARγflox/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.

Footnotes

  • Competing interests

    The authors declare no competing or financial interests.

  • Author contributions

    Study conception: S.V.-C., O.A., M.L., J.W.K., M.R. and T.-P.A.; hypotheses delineation and design of the study: S.V.-C., O.A., M.R. and T.-P.A.; performing experiments: S.V.-C., M.K., C.G.L., C.A., H.S., S.P.R., K.Y. and T.-P.A.; data analysis: S.V.-C., O.A., M.L.; data interpretation: S.V.-C., O.A., M.L., M.R. and T.-P.A.; drafting the manuscript: S.V.-C., O.A., M.R. and T.-P.A.; revising the manuscript: S.V.-C., O.A., M.L., M.K., C.A., C.G.L., H.S., S.P.R., K.Y., V.d.J.P., J.W.K., M.R. and T.-P.A. All authors have contributed to the manuscript and critically evaluated all versions of the manuscript. M.R. and T.-P.A. have equal senior authorship.

  • Funding

    This work was supported by Sigrid Juselius Foundation, Finnish Medical Foundation, Finnish Foundation for Cardiovascular Research, The Finnish Research Foundation of the Pulmonary Diseases (to S.V.-C.), The Finnish Research Foundation of Aarne and Aili Turunen (to S.V.-C.), Finnish Cultural Foundation [grant 00150083 to O.A.], Biomedicum Helsinki Foundation (to S.V.-C.), Finnish Foundation for Pediatric Research, and National Institutes of Health [grant number R01-HL087118 and R01-HL074186], and the Dwight and Vera Dunlevie Endowed Professorship (to M.R.).

  • Supplementary information

    Supplementary information available online at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.169011/-/DC1

  • Received January 19, 2015.
  • Accepted December 30, 2015.
  • © 2016. Published by The Company of Biologists Ltd
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Keywords

  • Endothelial cell
  • Angiogenesis
  • PPARγ
  • E2F1
  • GSKIP
  • Wnt signaling
  • Pulmonary hypertension
  • Osteopetrosis

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Research Article
Loss of PPARγ in endothelial cells leads to impaired angiogenesis
Sanna Vattulainen-Collanus, Oyediran Akinrinade, Molong Li, Minna Koskenvuo, Caiyun Grace Li, Shailaja P. Rao, Vinicio de Jesus Perez, Ke Yuan, Hirofumi Sawada, Juha W. Koskenvuo, Cristina Alvira, Marlene Rabinovitch, Tero-Pekka Alastalo
Journal of Cell Science 2016 129: 693-705; doi: 10.1242/jcs.169011
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Research Article
Loss of PPARγ in endothelial cells leads to impaired angiogenesis
Sanna Vattulainen-Collanus, Oyediran Akinrinade, Molong Li, Minna Koskenvuo, Caiyun Grace Li, Shailaja P. Rao, Vinicio de Jesus Perez, Ke Yuan, Hirofumi Sawada, Juha W. Koskenvuo, Cristina Alvira, Marlene Rabinovitch, Tero-Pekka Alastalo
Journal of Cell Science 2016 129: 693-705; doi: 10.1242/jcs.169011

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