RT Journal Article
SR Electronic
T1 Endothelial Cell–Targeted Deletion of PPAR<em>γ</em> Blocks Rosiglitazone-Induced Plasma Volume Expansion and Vascular Remodeling in Adipose Tissue
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 514
OP 523
DO 10.1124/jpet.118.250985
VO 368
IS 3
A1 Akiyama, Taro E.
A1 Skelhorne-Gross, Graham E.
A1 Lightbody, Elizabeth D.
A1 Rubino, Rachel E.
A1 Shi, Jia Yue
A1 McNamara, Lesley A.
A1 Sharma, Neelam
A1 Zycband, Emanuel I.
A1 Gonzalez, Frank J.
A1 Liu, Haiying
A1 Woods, John W.
A1 Chang, C. H.
A1 Berger, Joel P.
A1 Nicol, Christopher J. B.
YR 2019
UL http://jpet.aspetjournals.org/content/368/3/514.abstract
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 &gt;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.