In Vivo Magnetic Resonance Imaging‐Based Detection of Heterogeneous Endothelial Response in Thoracic and Abdominal Aorta to Short‐Term High‐Fat Diet Ascribed to Differences in Perivascular Adipose Tissue in Mice

Abstract

Background Long‐term feeding with a high‐fat diet (HFD) induces endothelial dysfunction in mice, but early HFD‐induced effects on endothelium have not been well characterized. Methods and Results Using an magnetic resonance imaging‐based methodology that allows characterization of endothelial function in vivo, we demonstrated that short‐term (2 weeks) feeding with a HFD to C57BL/6 mice or to E3L.CETP mice resulted in the impairment of acetylcholine‐induced response in the abdominal aorta (AA), whereas, in the thoracic aorta (TA), the acetylcholine‐induced response was largely preserved. Similarly, HFD resulted in arterial stiffness in the AA, but not in the TA. The difference in HFD‐induced response was ascribed to distinct characteristics of perivascular adipose tissue in the TA and AA, related to brown‐ and white‐like adipose tissue, respectively, as assessed by histology, immunohistochemistry, and Raman spectroscopy. In contrast, short‐term HFD‐induced endothelial dysfunction could not be linked to systemic insulin resistance, changes in plasma concentration of nitrite, or concentration of biomarkers of glycocalyx disruption (syndecan‐1 and endocan), endothelial inflammation (soluble form of vascular cell adhesion molecule 1, soluble form of intercellular adhesion molecule 1 and soluble form of E‐selectin), endothelial permeability (soluble form of fms‐like tyrosine kinase 1 and angiopoietin 2), and hemostasis (tissue plasminogen activator and plasminogen activator inhibitor 1). Conclusions Short‐term feeding with a HFD induces endothelial dysfunction in the AA but not in the TA, which could be ascribed to a differential response of perivascular adipose tissue to a HFD in the AA versus TA. Importantly, early endothelial dysfunction in the AA is not linked to elevation of classical systemic biomarkers of endothelial dysfunction.

Multi-omic signatures of atherogenic dyslipidaemia: pre-clinical target identification and validation in humans

“…Indeed, LDLR −/− mice, compared to ApoE −/− or ApoE/LDLR −/− , display modestly elevated plasma cholesterol levels and develop only mild atherosclerosis when fed a normal diet; however, they are highly responsive to high-fat/high cholesterol Western-type diets that affect the lipoprotein profile of these mice, amplifying atherosclerotic lesion development. Nonetheless, LDLR −/− mice possess some advantages over ApoE −/− mice in terms of comparison with human FH: (1) a more human-like lipid profile (as plasma cholesterol is carried more by LDL than in HDL particles but still not identical with typical human-like lipid pattern as reproduced in E3L.CETP mice [ 76 ]), (2) targeted inactivation of the LDL receptor does not impact inflammation as the deletion of ApoE, and (3) this model shares the characteristics observed in human FH (mutations in LDLR gene) [ 11 , 75 ]. Although our study demonstrates a relative agreement between species in terms of multi-omic signature identified, some caution should be taken in extrapolating the results from animals to humans.…”

Relationships Between Perivascular Adipose Tissue and Abdominal Aortic Aneurysms

“…The compositions of WAT and BAT in PVAT vary throughout the human body. PVAT contains mainly BAT in the thoracic aorta and mainly WAT in the abdominal aorta (6,24,25). In normal physiological conditions, PVAT releases vasoactive molecules (e.g., hydrogen peroxide, angiotensin, adiponectin, hydrogen sulfide, and nitric oxide) to attenuate agonist-induced vasoconstriction (26)(27)(28).…”

Systemic Administration of Insulin Receptor Antagonist Results in Endothelial and Perivascular Adipose Tissue Dysfunction in Mice

“…Assessment of protein biomarkers of endothelial dysfunction was performed using the microLC/MS-MRM method as described and used by our group previously [14,25,[29][30][31]. The panel included biomarkers of various aspects of endothelial dysfunction such as: glycocalyx disruption: syndecan-1 (SDC-1) and endocan (ESM-1); endothelial inflammation: soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular adhesion molecule 1 (sICAM-1), soluble form of E-selectin (sE-sel), soluble form of P-selectin (sP-sel); endothelial permeability: angiopoietin 1/2 (Angpt-1/2), soluble form of fms-like tyrosine kinase (sFLT-1) and hemostasis: von Willebrand factor (vWF), tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1).…”

“…PVAT positively regulates vascular function through the production of factors such as adiponectin, and its vasoprotective role is attenuated in obesity [13]. Interestingly, the role of PVAT has been connected with vascular pathologies, mostly in the context of obesity, fat overload and insulin resistance [14], but not with early hyperglycemia or specific alterations in insulin signaling. One possible reason for this limitation in understanding the role of PVAT in early hyperglycemia is the fact that diabetes research has been historically conducted with both pharmacological and genetic preclinical models that do not fully recapitulate the human condition, including pharmacologically induced T2D with streptozocin (STZ), or genetic model of type 2 diabetes of db/db mice.…”

“…Recently, a novel experimental approach to mimic the pathophysiology of T2D model was proposed, based on the administration of the insulin receptor antagonist (IRA), the S961 peptide, which has been shown to induce transient hyperglycemia and hyperinsulinemia in mice [15] and rats [16], as well as to elicit NADPH-dependent endothelial nitric oxide synthase (eNOS) uncoupling in rabbits [17] and microvascular complications in mice [18]. Given the accumulating evidence suggesting that PVAT's structural and functional alterations might contribute to endothelial dysfunction [19] and that brown adipose tissue (BAT) is able to rescue the endothelium [14], here we aimed to comprehensively verify the effects of a short-term, 2-week treatment with the S961 peptide, not only on endothelial but also PVAT function in the TA and AA in mice, using the state-of-the-art method for in vivo assessment of endothelial function, based on magnetic resonance imaging (MRI) with subsequent ex vivo analysis of the endothelium and PVAT.…”