PT  - JOURNAL ARTICLE
AU  - Akiyama, Taro E.
AU  - Skelhorne-Gross, Graham E.
AU  - Lightbody, Elizabeth D.
AU  - Rubino, Rachel E.
AU  - Shi, Jia Yue
AU  - McNamara, Lesley A.
AU  - Sharma, Neelam
AU  - Zycband, Emanuel I.
AU  - Gonzalez, Frank J.
AU  - Liu, Haiying
AU  - Woods, John W.
AU  - Chang, C. H.
AU  - Berger, Joel P.
AU  - Nicol, Christopher J. B.
TI  - Endothelial Cell–Targeted Deletion of PPAR<em>γ</em> Blocks Rosiglitazone-Induced Plasma Volume Expansion and Vascular Remodeling in Adipose Tissue
AID  - 10.1124/jpet.118.250985
DP  - 2019 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 514--523
VI  - 368
IP  - 3
4099  - http://jpet.aspetjournals.org/content/368/3/514.short
4100  - http://jpet.aspetjournals.org/content/368/3/514.full
SO  - J Pharmacol Exp Ther2019 Mar 01; 368
AB  - Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that represent an effective class of insulin-sensitizing agents; however, clinical use is associated with weight gain and peripheral edema. To elucidate the role of PPARγ expression in endothelial cells (ECs) in these side effects, EC-targeted PPARγ knockout (PpargΔEC) mice were placed on a high-fat diet to promote PPARγ agonist–induced plasma volume expansion, and then treated with the TZD rosiglitazone. Compared with Pparg-floxed wild-type control (Ppargf/f) mice, PpargΔEC treated with rosiglitazone are resistant to an increase in extracellular fluid, water content in epididymal and inguinal white adipose tissue, and plasma volume expansion. Interestingly, histologic assessment confirmed significant rosiglitazone-mediated capillary dilation within white adipose tissue of Ppargf/f mice, but not PpargΔEC mice. Analysis of ECs isolated from untreated mice in both strains suggested the involvement of changes in endothelial junction formation. Specifically, compared with cells from Ppargf/f mice, PpargΔEC cells had a 15-fold increase in focal adhesion kinase, critically important in EC focal adhesions, and >3-fold significant increase in vascular endothelial cadherin, the main component of focal adhesions. Together, these results indicate that rosiglitazone has direct effects on the endothelium via PPARγ activation and point toward a critical role for PPARγ in ECs during rosiglitazone-mediated plasma volume expansion.