Age-Dependent and -Independent Effects of Perivascular Adipose Tissue and Its Paracrine Activities during Neointima Formation

Abstract

Cardiovascular risk factors may act by modulating the composition and function of the adventitia. Here we examine how age affects perivascular adipose tissue (PVAT) and its paracrine activities during neointima formation. Aortic tissue and PVAT or primary aortic smooth muscle cells from male C57BL/6JRj mice aged 52 weeks (“middle-aged”) were compared to tissue or cells from mice aged 16 weeks (“adult”). Vascular injury was induced at the carotid artery using 10% ferric chloride. Carotid arteries from the middle-aged mice exhibited smooth muscle de-differentiation and elevated senescence marker expression, and vascular injury further aggravated media and adventitia thickening. Perivascular transplantation of PVAT had no effect on these parameters, but age-independently reduced neointima formation and lumen stenosis. Quantitative PCR analysis revealed a blunted increase in senescence-associated proinflammatory changes in perivascular tissue compared to visceral adipose tissue and higher expression of mediators attenuating neointima formation. Elevated levels of protein inhibitor of activated STAT1 (PIAS1) and lower expression of STAT1- or NFκB-regulated genes involved in adipocyte differentiation, inflammation, and apoptosis/senescence were present in mouse PVAT, whereas PIAS1 was reduced in the PVAT of patients with atherosclerotic vessel disease. Our findings suggest that age affects adipose tissue and its paracrine vascular activities in a depot-specific manner. PIAS1 may mediate the age-independent vasculoprotective effects of perivascular fat.

SIV Infection and the HIV Proteins Tat and Nef Induce Senescence in Adipose Tissue and Human Adipose Stem Cells, Resulting in Adipocyte Dysfunction

“…We propose that in VAT the p16 pathway of senescence [29] is activated in priority by SIV and its proteins rather than that using p53. Accordingly, recent data show that aging is not associated with p53 activation in VAT [30]. We found a significant effect both of SIV infection and of adipose tissue localization on p16 expression.…”

Perivascular Adipose Tissue as a Target for Antioxidant Therapy for Cardiovascular Complications

“…Moreover, aging promotes ROS production in PVAT, which subsequently contributes to aging-related vascular injury [77,78]. Elevated levels of a protein inhibitor of activated STAT1 (PIAS1) and lower expression of a signal transducer and activator of transcription 1 (STAT1)-or a nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFκB)-regulated genes involved in adipocyte differentiation, inflammation, and apoptosis are observed in PVAT surrounding the thoracic aorta of aged mice [79]. Senescence-accelerated mouse prone 8 (SAMP8), a mouse line that has accelerated aging, shows vascular dysfunction with associated hypertension and cognitive decline [80].…”

Role of Inflammation in Vascular Disease-Related Perivascular Adipose Tissue Dysfunction

“…In the mesenteric arteries of SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome, vascular dysfunction is compensated by a PVAT-dependent mechanism, which disappears with age ( 60 ). Compared with young C57BL/6JRj mice, middle-aged mice showed more PVAT hypertrophy ( 61 ); furthermore, the mean single adipocyte area in PVAT was significantly increased, while the expression level of protein inhibitor of activated signal transducer and activators of transcription 1 (a key negative regulator of inflammation) was decreased. These effects may contribute to age-related vascular diseases ( 61 ).…”

“…Compared with young C57BL/6JRj mice, middle-aged mice showed more PVAT hypertrophy (61); furthermore, the mean single adipocyte area in PVAT was significantly increased, while the expression level of protein inhibitor of activated signal transducer and activators of transcription 1 (a key negative regulator of inflammation) was decreased. These effects may contribute to age-related vascular diseases (61).…”