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Loss of PPAR gamma in endothelial cells leads to impaired angiogenesis JOURNAL OF CELL SCIENCE Vattulainen-Collanus, S., Akinrinade, O., Li, M., Koskenvuo, M., Li, C. G., Rao, S. P., Perez, V. D., Yuan, K., Sawada, H., Koskenvuo, J. W., Alvira, C., Rabinovitch, M., Alastalo, T. 2016; 129 (4): 693-705

Abstract

Tie2 promoter-mediated loss of peroxisome proliferator-activated receptor gamma (PPAR?) 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 (WT) 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 revealed E2F1 as a novel 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 GSK3ß interaction protein. In conclusion, PPAR? plays an important role in sustaining angiogenic potential in mature PMVECs through E2F1-mediated gene regulation.

View details for DOI 10.1242/jcs.169011

View details for Web of Science ID 000370240900006