PPARγ activation improves the microenvironment of perivascular adipose tissue and attenuates aortic stiffening in obesity

Abstract

Background Obesity-related cardiovascular risk, end points, and mortality are strongly related to arterial stiffening. Current therapeutic approaches for arterial stiffening are not focused on direct targeting within the vessel. Perivascular adipose tissue (PVAT) surrounding the artery has been shown to modulate vascular function and inflammation. Peroxisome proliferator-activated receptor γ (PPARγ) activation significantly decreases arterial stiffness and inflammation in diabetic patients with coronary artery disease. Thus, we hypothesized that PPARγ activation alters the PVAT microenvironment, thereby creating a favorable environment for the attenuation of arterial stiffening in obesity. Methods Obese ob/ob mice were used to investigate the effect of PPARγ activation on the attenuation of arterial stiffening. Various cell types, including macrophages, fibroblasts, adipocytes, and vascular smooth muscle cells, were used to test the inhibitory effect of pioglitazone, a PPARγ agonist, on the expression of elastolytic enzymes. Results PPARγ activation by pioglitazone effectively attenuated arterial stiffening in ob/ob mice. This beneficial effect was not associated with the repartitioning of fat from or changes in the browning of the PVAT depot but was strongly related to improvement of the PVAT microenvironment, as evidenced by reduction in the expression of pro-inflammatory and pro-oxidative factors. Pioglitazone treatment attenuated obesity-induced elastin fiber fragmentation and elastolytic activity and ameliorated the obesity-induced upregulation of cathepsin S and metalloproteinase 12, predominantly in the PVAT. In vitro, pioglitazone downregulated Ctss and Mmp12 in macrophages, fibroblasts, and adipocytes—cell types residing within the adventitia and PVAT. Ultimately, several PPARγ binding sites were found in Ctss and Mmp12 in Raw 264.7 and 3T3-L1 cells, suggesting a direct regulatory mechanism by which PPARγ activation repressed the expression of Ctss and Mmp-12 in macrophages and fibroblasts. Conclusions PPARγ activation attenuated obesity-induced arterial stiffening and reduced the inflammatory and oxidative status of PVAT. The improvement of the PVAT microenvironment further contributed to the amelioration of elastin fiber fragmentation, elastolytic activity, and upregulated expression of Ctss and Mmp12. Our data highlight the PVAT microenvironment as an important target against arterial stiffening in obesity and provide a novel strategy for the potential clinical use of PPARγ agonists as a therapeutic against arterial stiffness through modulation of PVAT function.

A Cell Atlas of Thoracic Aortic Perivascular Adipose Tissue: a focus on mechanotransducers

“…activator pioglitazone improved PVAT microenvironment of the ob/ob mouse to potentially reduce aortic stiffness. 40 These findings are consistent with the serendipitous discovery in the PPAR smooth muscle cell specific knockout mouse. In this KO mouse, PVAT did not develop around the thoracic aorta and the KO mouse had a higher pulse wave velocity, a surrogate of aortic stiffness, than the WT.…”

Novel Genes Potentially Involved in Fibroblasts of Diabetic Wound

“…High risk of wound infection and healing failure was found in diabetes, and the abnormal function of fibroblasts was assumed as a major issue contributing to the delayed wound healing [9][10][11]. Noticeably, fibroblasts exert an important role in wound inflammatory response by release of various antibacterial regulators, providing a robust defense of skin against infections [12][13][14]. Diabetes patients are susceptible to infections due to the dysregulated function of the T cells, leading to the overactivated tissue inflammation.…”

Exploring the Relationship of Perivascular Adipose Tissue Inflammation and the Development of Vascular Pathologies

“…Deletion of PPAR- γ during BAT adipogenesis impairs PVAT development and increases local inflammation, which often leads to the progression of atheromatous plaque and myocardial injury in vivo [ 12 , 13 ]. The activation of PPAR- γ has been shown to attenuate arterial stiffening and reduce inflammatory and oxidative stress in the PVAT of obese mice [ 14 ]. These findings highlight the significant role of PPAR- γ in PVAT in modulating inflammation and risk of vascular diseases.…”