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

Loss of PPARγ in endothelial cells leads to impaired angiogenesis.

Author information

1
Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland.
2
Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland Institute of Biomedicine, University of Helsinki, Helsinki 00290, Finland.
3
The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.
4
Children's Hospital Helsinki, Division of Hematology-Oncology and Stem Cell Transplantation, University of Helsinki and Helsinki University Central Hospital, 00290 Helsinki, Finland.
5
Department of Pediatrics, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute Stanford University, Stanford, CA 94305, USA.
6
Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA.
7
Department of Pediatrics, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute Stanford University, Stanford, CA 94305, USA Department of Pediatrics, Mie University Graduate School of Medicine, Mie 5148507, Japan.
8
Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland Department of Clinical Physiology and Nuclear Medicine, HUS Medical Imaging Center, Helsinki University Central Hospital and University of Helsinki, 00290 Helsinki, Finland.
9
Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland tero-pekka.alastalo@helsinki.fi.

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 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

PMID:
26743080
PMCID:
PMC5108588
DOI:
10.1242/jcs.169011
[Indexed for MEDLINE]
Free PMC Article

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