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Loss of PPAR? in endothelial cells leads to impaired angiogenesis.

ABSTRACT: Tie2-promoter-mediated loss of peroxisome proliferator-activated receptor gamma (PPAR?, also known as PPARG) in mice leads to osteopetrosis and pulmonary arterial hypertension. Vascular disease is associated with loss of PPAR? in pulmonary microvascular endothelial cells (PMVEC); we evaluated the role of PPAR? in PMVEC functions, such as angiogenesis and migration. The role of PPAR? in angiogenesis was evaluated in Tie2CrePPAR?(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 PPAR?. Tie2CrePPAR?(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 PPAR? attenuates the migration and angiogenic capacity of mature PMVECs. PPAR?-deficient human PMVECs showed a similar migration defect in culture. Bioinformatic and experimental analyses newly revealed E2F1 as a target of PPAR? in the regulation of PMVEC migration. Disruption of the PPAR?-E2F1 axis was associated with a dysregulated Wnt pathway related to the GSK3B interacting protein (GSKIP). In conclusion, PPAR? plays an important role in sustaining angiogenic potential in mature PMVECs through E2F1-mediated gene regulation.

SUBMITTER: Vattulainen-Collanus S 

PROVIDER: S-EPMC5108588 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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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 se  ...[more]

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