scholarly journals Perivascular adipose tissue‐derived stromal cells contribute to vascular remodeling during aging

Aging Cell ◽  
2019 ◽  
Vol 18 (4) ◽  
Author(s):  
Xiao‐Xi Pan ◽  
Cheng‐Chao Ruan ◽  
Xiu‐Ying Liu ◽  
Ling‐Ran Kong ◽  
Yu Ma ◽  
...  
2021 ◽  
Vol 22 (5) ◽  
pp. 2649
Author(s):  
Alexis N. Orr ◽  
Janice M. Thompson ◽  
Janae M. Lyttle ◽  
Stephanie W. Watts

Transglutaminases (TGs) are crosslinking enzymes best known for their vascular remodeling in hypertension. They require calcium to form an isopeptide bond, connecting a glutamine to a protein bound lysine residue or a free amine donor such as norepinephrine (NE) or serotonin (5-HT). We discovered that perivascular adipose tissue (PVAT) contains significant amounts of these amines, making PVAT an ideal model to test interactions of amines and TGs. We hypothesized that transglutaminases are active in PVAT. Real time RT-PCR determined that Sprague Dawley rat aortic, superior mesenteric artery (SMA), and mesenteric resistance vessel (MR) PVATs express TG2 and blood coagulation Factor-XIII (FXIII) mRNA. Consistent with this, immunohistochemical analyses support that these PVATs all express TG2 and FXIII protein. The activity of TG2 and FXIII was investigated in tissue sections using substrate peptides that label active TGs when in a catalyzing calcium solution. Both TG2 and FXIII were active in rat aortic PVAT, SMAPVAT, and MRPVAT. Western blot analysis determined that the known TG inhibitor cystamine reduced incorporation of experimentally added amine donor 5-(biotinamido)pentylamine (BAP) into MRPVAT. Finally, experimentally added NE competitively inhibited incorporation of BAP into MRPVAT adipocytes. Further studies to determine the identity of amidated proteins will give insight into how these enzymes contribute to functions of PVAT and, ultimately, blood pressure.


Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Roxanne Fernandes ◽  
Patricia A Perez Bonilla ◽  
Hannah Garver ◽  
James J Galligan ◽  
Gregory D Fink ◽  
...  

Obesity associated hypertension in rodent models is commonly associated with altered vascular reactivity to sympathetic neurotransmitters and inflammation-induced vascular remodeling/fibrosis. Dahl salt-sensitive (SS) rats exhibit elevated sympathetic activity and vascular remodeling. We hypothesized that diet-induced obesity in Dahl SS rats would promote hypertension, vascular dysfunction and remodeling/fibrosis. Male Dahl SS rats were placed on high fat diet (HFD, 60% kcal from fat with final concentrations of 0.33% NaCl and 1% K + , n=5) or normal-fat diet (NFD; 10% kcal from fat, 0.24% NaCl, 0.36% K + , n=5) for 24-26 weeks after weaning (3 weeks of age). Compared with NFD rats, HFD rats displayed severe hypertension (MAP, 165±4 mmHg vs 133±6 mmHg, P<0.05), higher body-weight (470±6g vs 433±7g, P<0.05), and hyperlipidemia (cholesterol, 211±22 mg/dl vs 138±23 mg/dl, P=0.05). HFD rats did not show significant changes in plasma levels of fasting glucose (85±5 mg/dl vs 75±5 mg/dl), insulin (2.6±0.8 ng/ml vs 2.2±1.1 ng/ml), leptin (0.77±0.18 ng/ml vs 0.44±0.06 ng/ml), or aldosterone (249±3 pg/ml vs 234±3 pg/ml) (all P>0.05). HFD did not affect pressurized mesenteric arterial (~300 μm inner diameter, 60 mmHg) reactivity to norepinephrine or ATP in vitro . Pressurized mesenteric arteries from HFD rats displayed thicker walls (Ca 2+ free buffer, 40±1 μm vs 36±1 μm, P<0.05), but showed slightly increased distensibility. Morphological studies did not reveal greater fibrosis in adventitia of mesenteric, intrarenal and coronary arteries from HFD rats. However, HFD induced inflammation in mesenteric perivascular adipose tissue, as shown by increased CD3 positive cell infiltration and histological evidence of fibrosis and angiogenesis. Our studies indicate that HFD in male Dahl SS rats promotes hypertension, perivascular adipose tissue inflammation and vascular remodeling, but not vascular fibrosis. Alteration of vascular contractility to sympathetic neurotransmitters, however, is not required for obesity associated hypertension in Dahl SS rats.


2019 ◽  
Vol 33 (11) ◽  
pp. 12704-12722 ◽  
Author(s):  
Xinzhi Li ◽  
Laurel L. Ballantyne ◽  
Ying Yu ◽  
Colin D. Funk

Author(s):  
Sophie N Saxton ◽  
Lauren K Toms ◽  
Robert G Aldous ◽  
Sarah B Withers ◽  
Jacqueline Ohanian ◽  
...  

AbstractPurposePerivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating vascular tone. This effect is mediated via sympathetic nervous stimulation of PVAT by a mechanism which involves noradrenaline uptake through organic cation transporter 3 (OCT3) and β3-adrenoceptor-mediated adiponectin release. In obesity, autonomic dysfunction occurs, which may result in a loss of PVAT function and subsequent vascular disease. Accordingly, we have investigated abnormalities in obese PVAT, and the potential for exercise in restoring function.MethodsVascular contractility to electrical field stimulation (EFS) was assessed ex vivo in the presence of pharmacological tools in ±PVAT vessels from obese and exercised obese mice. Immunohistochemistry was used to detect changes in expression of β3-adrenoceptors, OCT3 and tumour necrosis factor-α (TNFα) in PVAT.ResultsHigh fat feeding induced hypertension, hyperglycaemia, and hyperinsulinaemia, which was reversed using exercise, independent of weight loss. Obesity induced a loss of the PVAT anti-contractile effect, which could not be restored via β3-adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing β3-adrenoceptor and OCT3 expression, which were downregulated in obesity. Furthermore, the vasodilator effects of adiponectin were restored.ConclusionLoss of neutrally mediated PVAT anti-contractile function in obesity will contribute to the development of hypertension and type II diabetes. Exercise training will restore function and treat the vascular complications of obesity.


Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1908
Author(s):  
Anna Labedz-Maslowska ◽  
Agnieszka Szkaradek ◽  
Tomasz Mierzwinski ◽  
Zbigniew Madeja ◽  
Ewa Zuba-Surma

Adipose tissue (AT) represents a commonly used source of mesenchymal stem/stromal cells (MSCs) whose proregenerative potential has been widely investigated in multiple clinical trials worldwide. However, the standardization of the manufacturing process of MSC-based cell therapy medicinal products in compliance with the requirements of the local authorities is obligatory and will allow us to obtain the necessary permits for product administration according to its intended use. Within the research phase (RD), we optimized the protocols used for the processing and ex vivo expansion of AT-derived MSCs (AT-MSCs) for the development of an Advanced Therapy Medicinal Product (ATMP) for use in humans. Critical process parameters (including, e.g., the concentration of enzyme used for AT digestion, cell culture conditions) were identified and examined to ensure the high quality of the final product containing AT-MSCs. We confirmed the identity of isolated AT-MSCs as MSCs and their trilineage differentiation potential according to the International Society for Cellular Therapy (ISCT) recommendations. Based on the conducted experiments, in-process quality control (QC) parameters and acceptance criteria were defined for the manufacturing of hospital exemption ATMP (HE-ATMP). Finally, we conducted a validation of the manufacturing process in a GMP facility. In the current study, we presented a process approach leading to the optimization of processing and the ex vivo expansion of AT-MSCs for the development of ATMP for use in humans.


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