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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