Background and Aims:
Previous investigations have demonstrated that Endothelin B receptor (ETB)-expressing resident LYVE-1 macrophages serve as pivotal regulators of endothelin-1 (ET-1) clearance and act as modulators of vascular homeostasis, exerting protective effects on the progression of atherosclerosis. This study aimed to elucidate the role of ETB expressed by resident macrophages on metabolic and vascular alterations induced by diet-induced obesity.
Methods and Results:
Using a genetically engineered murine model with targeted ETB deletion in resident LYVE-1+ macrophages (Lyve-1
cre/wtEdnrB
flox/flox), animals were subjected to a 18-week high-fat diet regimen (Figure 1). Lyve-1
cre/wtEdnrB
flox/flox mice displayed significantly greater body weight gain, increased liver mass and epididymal white adipose tissue hypertrophy compared to floxed control while plasma cholesterol levels were comparable. Histological examination revealed increased CD68+ macrophage crown-like structures, indicative of amplified adipose inflammation. Furthermore, ET-1 concentrations were significantly elevated in plasma, adipose, and hepatic tissues of Lyve-1
cre/wtEdnrB
flox/flox mice. Vascular assessment demonstrated exacerbated remodeling characterized by decreased aortic medial smooth muscle actin density and reduced adventitial collagen I deposition in mice lacking ETB on LYVE-1+ macrophages. In contrast, alterations in aortic luminal size and diameter were not significantly different.
Conclusions:
These findings substantiate the critical role of ETB-expressing resident macrophages in mediating ET-1 clearance and highlight their importance in mitigating obesity-associated vascular remodeling and dysfunction. Therapeutic strategies targeting ETB signaling pathways in macrophages may hold promise for ameliorating metabolic and cardiovascular pathologies.
