Endothelial Cell–Targeted Deletion of PPARγBlocks Rosiglitazone-Induced Plasma Volume Expansion and Vascular Remodeling in Adipose Tissue

Abstract

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor g (PPARg) 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 PPARg expression in endothelial cells (ECs) in these side effects, EC-targeted PPARg knockout (Pparg DEC ) mice were placed on a high-fat diet to promote PPARg agonist-induced plasma volume expansion, and then treated with the TZD rosiglitazone. Compared with Pparg-floxed wild-type control (Pparg f/f ) mice, Pparg DEC 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 rosiglitazonemediated capillary dilation within white adipose tissue of Pparg f/f mice, but not Pparg DEC 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 Pparg f/f mice, Pparg DEC 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 PPARg activation and point toward a critical role for PPARg in ECs during rosiglitazone-mediated plasma volume expansion.

The Suv420h histone methyltransferases regulate PPAR-γ and energy expenditure in response to environmental stimuli

“…An additional mechanism influencing body weight gain upon systemic PPAR-γ activation is increased body fluid volume due to water retention. In addition, this process is tissue and cell type specific, given that PPAR-γ deletion selectively in kidney or in endothelial cells blocks TZD-induced weight gain in animal models ( 54 – 56 ). TZD-mediated activation of PPAR-γ also leads to increased feeding due to a tissue-specific activity mediated by PPAR-γ in the central nervous system ( 57 ).…”

“…Chromatin was extracted from iBAT as described in Materials and Methods and used for ChIP. is tissue and cell type specific, given that PPAR- deletion selectively in kidney or in endothelial cells blocks TZD-induced weight gain in animal models (54)(55)(56). TZD-mediated activation of PPAR- also leads to increased feeding due to a tissue-specific activity mediated by PPAR- in the central nervous system (57).…”

Bioinformatics analysis reveals the potential target of rosiglitazone as an antiangiogenic agent for breast cancer therapy

“…PPAR signaling has implications in the pathophysiology of skeletal muscle dysfunction in patients with breast cancer [ 44 ]. RGZ activates PPARg signaling in endothelial cells [ 45 ]. RGZ inhibits metastasis and migration, decreases MMP-2 expression, and prevents angiogenesis by blocking the vascular endothelial growth factor (VEGF) pathway in SGC-7901 gastric cancer cells [ 46 ].…”