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 angiogenesisassociated 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.

PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis

“…We and others showed that PPARγ promotes endothelial survival and regeneration (Alastalo et al, 2011; Vattulainen-Collanus et al, 2016). In a transgenic mouse with deficient endothelial PPARγ, pulmonary hypertension and adverse vascular remodeling did not reverse following re-exposure to room air after chronic hypoxia (Guignabert et al, 2009).…”

Genetic profile of isolated congenital diaphragmatic hernia revealed by targeted next‐generation sequencing

“…PPARG is involved in neuronal development, inflammation, keratinocyte differentiation, and epidermal barrier recovery . In addition, PPARG contributes to lung maturation and to pulmonary angiogenesis . Concordantly, PPARGC1 activates vascular endothelial growth factor expression VEGF and is important for angiogenesis and neovascularization .…”

PPARγ Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats

“…* P < 0.05; ** P < 0.01; *** P < 0.001. of nuclear receptors, has been proved to ameliorate PAH by inhibiting PASMCs proliferation, improving ECs function, alleviating inflammation, etc. [11][12][13][14] In this experiment, the direct effect of PPARγ on RV was examined.…”

“…[7][8][9] Accumulating evidence demonstrated that activation of PPARγ may be a novel PAH therapeutic target. 10) PPARγ agonist rosiglitazone (Rosi) has been proved to alleviate PAH in rats, including regulating endothelial dysfunction, 11) sustaining angiogenic potential in mature pulmonary microvascular endotheliai cells (PMVECs), 12) preventing PASMCs proliferation, 13,14) etc. However, the mechanisms of PPARγ's effect on PAH-induced RVF remain unknown.…”