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Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-? deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis.

ABSTRACT: Perivascular adipose tissue (PVAT) surrounds most vessels and shares common features with brown adipose tissue (BAT). Although adaptive thermogenesis in BAT increases energy expenditure and is beneficial for metabolic diseases, little is known about the role of PVAT in vascular diseases such as atherosclerosis. We hypothesize that the thermogenic function of PVAT regulates intravascular temperature and reduces atherosclerosis.PVAT shares similar structural and proteomics with BAT. We demonstrated that PVAT has thermogenic properties similar to BAT in response to cold stimuli in vivo. Proteomics analysis of the PVAT from mice housed in a cold environment identified differential expression in proteins highly related to cellular metabolic processes. In a mouse model deficient in peroxisome proliferator-activated receptor-? in smooth muscle cells (SMPG KO mice), we uncovered a complete absence of PVAT surrounding the vasculature, likely caused by peroxisome proliferator-activated receptor-? deletion in the perivascular adipocyte precursor cells as well. Lack of PVAT, which results in loss of its thermogenic activity, impaired vascular homeostasis, which caused temperature loss and endothelial dysfunction. We further showed that cold exposure inhibits atherosclerosis and improves endothelial function in mice with intact PVAT but not in SMPG KO mice as a result of impaired lipid clearance. Proinflammatory cytokine expression in PVAT is not altered on exposure to cold. Finally, prostacyclin released from PVAT contributes to the vascular protection against endothelial dysfunction.PVAT is a vasoactive organ with functional characteristics similar to BAT and is essential for intravascular thermoregulation of cold acclimation. This thermogenic capacity of PVAT plays an important protective role in the pathogenesis of atherosclerosis.

SUBMITTER: Chang L

PROVIDER: S-EPMC3493564 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-γ deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis.

Chang Lin L Villacorta Luis L Li Rongxia R Hamblin Milton M Xu Wei W Dou Chunyan C Zhang Jifeng J Wu Jiarui J Zeng Rong R Chen Y Eugene YE

Circulation 20120801 9

<h4>Background</h4>Perivascular adipose tissue (PVAT) surrounds most vessels and shares common features with brown adipose tissue (BAT). Although adaptive thermogenesis in BAT increases energy expenditure and is beneficial for metabolic diseases, little is known about the role of PVAT in vascular diseases such as atherosclerosis. We hypothesize that the thermogenic function of PVAT regulates intravascular temperature and reduces atherosclerosis.<h4>Methods and results</h4>PVAT shares similar str ...[more]

PMID: 22855570

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Project description:Peroxisome proliferator-activated receptor-? (PPAR?) plays an important role in the vasculature; however, the role of PPAR? in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPAR? in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPAR?-mediated signaling pathways that may prevent the development of AAA.We determined whether periaortic application of CaCl(2) renders vascular SMC-selective PPAR? knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.There is evidence of increased vessel dilatation in the abdominal aorta 6 weeks after 0.25M periaortic CaCl(2) application in SMPG KO mice compared with littermate controls (1.4 ± 0.3 mm [n = 8] vs 1.1 ± 0.2 mm [n = 7]; P = .000119). Results from SMPG KO mice indicate medial layer elastin degradation was greater 6 weeks after abluminal application of CaCl(2) to the abdominal aorta (P < .01). Activated cathepsin S, a potent elastin-degrading enzyme, was increased in SMPG KO mice vs wild-type controls. To further identify a role of PPAR? signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPAR? overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPAR? bound to a peroxisome proliferator-activated receptor response element (PPRE) -141 to -159 bp upstream of the cathepsin S gene sequence in mouse aortic SMCs. Also, adenoviral-mediated PPAR? overexpression and knockdown in cultured rat aortic SMCs decreases (P = .013) and increases (P = .018) expression of activated cathepsin S. Finally, immunohistochemistry demonstrated a greater inflammatory infiltrate in SMPG KO mouse aortas, as evidenced by elevations in F4/80 and tumor necrosis factor-? expression.In this study, we identify PPAR? as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPAR? in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPAR? activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.

Project description:Background: Perivascular adipose tissue (PVAT), which surrounds most vessels, is de facto a distinct functional vascular layer actively contributing to vascular function and dysfunction. PVAT contributes to aortic remodeling by producing and releasing a large number of undetermined or less characterized factors that could target endothelial cells and vascular smooth muscle cells, and herein contribute to the maintenance of vessel homeostasis. Loss of PVAT in mice enhances atherosclerosis, but a causal relationship between PVAT and atherosclerosis and the possible underlying mechanisms remain to be addressed. The CDGSH iron sulfur domain 1 protein (referred to as mitoNEET), a mitochondrial outer membrane protein, regulates oxidative capacity and adipose tissue browning. The roles of mitoNEET in PVAT, especially in the development of atherosclerosis, are unknown. Methods: The brown adipocyte-specific mitoNEET transgenic mice were subjected to cold environmental stimulus. The metabolic rates and PVAT-dependent thermogenesis were investigated. Additionally, the brown adipocyte-specific mitoNEET transgenic mice were cross-bred with ApoE knockout mice. The ensuing mice were subsequently subjected to cold environmental stimulus and high cholesterol diet challenge for 3 months. The development of atherosclerosis was investigated. Results: Our data show that mitoNEET mRNA was downregulated in PVAT of both peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α)- and beta (Pgc1β)-knockout mice which are sensitive to cold. MitoNEET expression was higher in PVAT of wild type mice and increased upon cold stimulus. Transgenic mice with overexpression of mitoNEET in PVAT were cold resistant, and showed increased expression of thermogenic genes. ApoE knockout mice with mitoNEET overexpression in PVAT showed significant downregulation of inflammatory genes and showed reduced atherosclerosis development upon high fat diet feeding when kept in a 16°C environment. Conclusion: mitoNEET in PVAT is associated with PVAT-dependent thermogenesis and prevents atherosclerosis development. The results of this study provide new insights on PVAT and mitoNEET biology and atherosclerosis in cardiovascular diseases.

Dataset Information

Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-? deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis.

Publications

Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-γ deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis.

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