Endothelin A Receptor Activation on Vascular Smooth Muscle Cells Mediates Visceral Adipose Tissue Inflammation in an Obese Mouse Model

Abstract

Obesity causes a pro-inflammatory shift in visceral adipose tissue immune cells that is thought to promote adipocyte dysfunction and obesity pathophysiology. Endothelin-1 (ET-1) is a small peptide produced mostly by endothelial cells that causes inflammation in diseases including a number of nephropathies and autoimmune diseases. ET-1 is increased in obese patients and in rodent models of obesity. Our lab has demonstrated that mice fed high fat diet (HFD) have an increase in visceral adipose tissue CD4+ and CD8+ T cells and a reduction in anti-inflammatory eosinophils that is attenuated by treatment with an ET-1 type A receptor (ETAR) antagonist; however, the mechanisms by which ET-1 leads to inflammation remain unknown. The ETAR is highly abundant on vascular smooth muscle cells (VSMC), where activation causes a significant increase in pro-inflammatory interleukin-6 production. We hypothesized that elevated ET-1 production in visceral adipose causes a pro-inflammatory shift in tissue immune cells by activating VSMC ETAR. To test this hypothesis, 8-week-old floxed control and vascular smooth muscle cell-specific ETA knockout (SMAKO) mice were placed on either normal (n=5 and 3 for control and SMAKO respectively) or high-fat diet (n=6 and 4 for control and SMAKO respectively) for 12 weeks. Tissue immune cells were quantified by flow cytometry. As expected, HFD fed mice had significantly increased body weight, lean mass, and fat mass, as measured by EchoMRI, compared to NMD fed mice; however, there was no detectable difference due to genotype. There was a significant increase in CD4+ T cells (control NMD: 2.45 ± 0.28 vs. control HFD: 4.37 ± 0.80 % of CD45+ cells; SMAKO NMD: 0.94 ± 0.52 vs. SMAKO HFD: 2.24 ± 0.40 % of CD45+ cells; pint=0.63, pdiet=0.02*, pgenotype=0.01*) and CD8+ T cells (control NMD: 0.49 ± 0.10 vs. control HFD: 2.02 ± 0.59 % of CD45+ cells; SMAKO NMD: 0.12 ± 0.07 vs. SMAKO HFD: 0.52 ± 0.07 % of CD45+ cells; pint=0.20, pdiet=0.04*, pgenotype=0.04*) that was significantly attenuated in SMAKO mice. In addition, HFD fed control mice had a greater reduction in eosinophils compared to NMD floxed control. The reduction in eosinophils was attenuated in SMAKO (control NMD: 5.28 ± 2.01 vs. control HFD: 1.28 ± 0.07 % of CD45+ cells; SMAKO NMD: 5.92 ± 0.94 vs. SMAKO HFD: 4.49 ± 1.60 % of CD45+ cells; pint=0.42, pdiet=0.09, pgenotype=0.23). These data suggest that ET-1-induced adipose tissue inflammation in obese mice occurs via activation of ETAR on VSMCs. R01DK124437, P30GM149404, and T32HL105324. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.