RT Journal Article SR Electronic T1 Endothelial cell targeted deletion of PPARγ 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 jpet.118.250985 DO 10.1124/jpet.118.250985 A1 Taro E. Akiyama A1 Graham E. Skelhorne-Gross A1 Elizabeth D. Lightbody A1 Rachel E. Rubino A1 Jia Yue Shi A1 Lesley A. McNamara A1 Neelam Sharma A1 Emanuel I. Zycband A1 Frank J. Gonzalez A1 Haiying Liu A1 John W. Woods A1 C. H. Chang A1 Joel P. Berger A1 Christopher J.B. Nicol YR 2019 UL http://jpet.aspetjournals.org/content/early/2019/01/03/jpet.118.250985.abstract AB Thiazolidinediones (TZDs) are 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-specific PPARγ knockout (PpargΔEC) mice were placed on high fat diet to promote PPARγ agonist-induced plasma volume expansion, and then treated with the TZD rosiglitazone. Compared to 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, histological 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 suggests the involvement of changes in endothelial junction formation. Specifically, compared to cells from Ppargf/f mice, PpargΔEC cells have 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 towards a critical role for PPARγ in ECs during rosiglitazone-mediated plasma volume expansion.