Loss of PPARγ in endothelial cells leads to impaired angiogenesis

被引：42

作者：

Vattulainen-Collanus, Sanna ^{[1
,2
]}

Akinrinade, Oyediran ^{[1
,3
]}

Li, Molong ^{[4
,5
]}

Koskenvuo, Minna ^{[2
,6
]}

Li, Caiyun Grace ^{[7
]}

Rao, Shailaja P. ^{[7
]}

Perez, Vinicio de Jesus ^{[8
]}

Yuan, Ke ^{[8
]}

Sawada, Hirofumi ^{[7
,9
]}

Koskenvuo, Juha W. ^{[5
,10
,11
]}

Alvira, Cristina ^{[7
]}

Rabinovitch, Marlene ^{[7
]}

Alastalo, Tero-Pekka ^{[1
,2
]}

机构：

[1] Univ Helsinki, Pediat Cardiol, Childrens Hosp Helsinki, FIN-00290 Helsinki, Finland

[2] Univ Helsinki, Cent Hosp, FIN-00290 Helsinki, Finland

[3] Univ Helsinki, Inst Biomed, FIN-00290 Helsinki, Finland

[4] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA

[5] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland

[6] Univ Helsinki, Div Hematol Oncol & Stem Cell Transplantat, Childrens Hosp Helsinki, FIN-00290 Helsinki, Finland

[7] Stanford Univ, Wall Ctr Pulm Vasc Dis, Dept Pediat, Cardiovasc Inst, Stanford, CA 94305 USA

[8] Stanford Univ, Div Pulm & Crit Care Med, Stanford, CA 94305 USA

[9] Mie Univ, Grad Sch Med, Dept Pediat, Tsu, Mie 5148507, Japan

[10] Univ Helsinki, Cent Hosp, HUS Med Imaging Ctr, Dept Clin Physiol & Nucl Med, FIN-00290 Helsinki, Finland

[11] Univ Helsinki, FIN-00290 Helsinki, Finland

来源：

JOURNAL OF CELL SCIENCE | 2016年 / 129卷 / 04期

基金：

美国国家卫生研究院;

关键词：

Endothelial cell; Angiogenesis; PPAR gamma; E2F1; GSKIP; Wnt signaling; Pulmonary hypertension; Osteopetrosis; ACTIVATED RECEPTOR-GAMMA; DIFFERENTIAL EXPRESSION ANALYSIS; GROWTH-FACTOR; PROGENITOR CELLS; BONE-MARROW; PULMONARY-HYPERTENSION; GENETIC-HETEROGENEITY; WNT; PROTEIN; MOBILIZATION;

D O I：

10.1242/jcs.169011

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：693 / 705

页数：13