Abstract

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.