title: Loss of PPARγ in endothelial cells leads to impaired angiogenesis.
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.
authors.affiliation: Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Vattulainen-Collanus
authors.affiliation: 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.
authors.forename: Oyediran
authors.initials: O
authors.lastname: Akinrinade
authors.affiliation: 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.
authors.forename: Molong
authors.initials: M
authors.lastname: Li
authors.affiliation: Children's Hospital Helsinki, Division of Hematology-Oncology and Stem Cell Transplantation, University of Helsinki and Helsinki University Central Hospital, 00290 Helsinki, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Koskenvuo
authors.affiliation: Department of Pediatrics, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute Stanford University, Stanford, CA 94305, USA.
authors.forename: Caiyun Grace
authors.initials: CG
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute Stanford University, Stanford, CA 94305, USA.
authors.forename: Shailaja P
authors.initials: SP
authors.lastname: Rao
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Vinicio
authors.initials: V
authors.lastname: de Jesus Perez
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawada
authors.affiliation: 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.
authors.forename: Juha W
authors.initials: JW
authors.lastname: Koskenvuo
authors.affiliation: Department of Pediatrics, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute Stanford University, Stanford, CA 94305, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Alvira
authors.affiliation: Department of Pediatrics, Wall Center for Pulmonary Vascular Disease, Cardiovascular Institute Stanford University, Stanford, CA 94305, USA.
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
authors.affiliation: Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland tero-pekka.alastalo@helsinki.fi.
authors.forename: Tero-Pekka
authors.initials: TP
authors.lastname: Alastalo
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D002478:Cells, Cultured; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000098:blood supply; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D047495:PPAR gamma; D051176:beta Catenin
keywords: Angiogenesis; E2F1; Endothelial cell; GSKIP; Osteopetrosis; PPARγ; Pulmonary hypertension; Wnt signaling