Abstract
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.
Footnotes
- Received May 28, 2018.
- Accepted December 6, 2018.
↵1 T.E.A. and G.E.S.-G. contributed equally to this work.
This work was supported by funding from Merck Research Laboratories to T.E.A., L.A.M., N.S., E.I.Z., H.L., J.W.W., C.H.C., and J.P.B., and the Canadian Breast Cancer Foundation, Ontario Chapter [#369649] to C.J.B.N. This research was supported in part by the Intramural Research Program of the National Institutes of Health [National Cancer Institute]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
This article was prepared while T.E.A. was employed at Merck & Co. The opinions expressed in this article are the author’s own and do not reflect the view of the Food and Drug Administration, the Department of Health and Human Services, or the United States government.
↵This article has supplemental material available at jpet.aspetjournals.org.
- U.S. Government work not protected by U.S. copyright