Loss of PPARγ in endothelial cells leads to impaired angiogenesis

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