Melanocortin-4 receptor in macrophages attenuated angiotensin II-induced abdominal aortic aneurysm in mice

Abstract

Obesity is recognized as an independent risk factor for abdominal aortic aneurysm (AAA). While mutations in the melanocortin-4 receptor (MC4R) gene is the most common cause of obesity caused by mutations in a single gene, the link between MC4R function and vascular disease has still remained unclear. Here, by using melanocortin-4 receptor (MC4R) deficient mice, we confirmed MC4R deficiency promotes AAA and atherosclerosis. We demonstrated the contribution of two novel factors towards vascular vulnerability in this model: leptin signaling in vascular smooth muscle cells (VSMCs) and loss of MC4R signaling in macrophages. Leptin was shown to promote vascular vulnerability via PI3K-dependent upregulation of Spp1 expression in VSMC. Additionally, Ang II-induced AAA incidence was significantly reduced when MC4R gene expression was myeloid cell-specifically rescued in MC4R deficient (MC4RTB/TB) mice. Ex vivo analysis showed a suppression in NF-κB activity in bone marrow-derived macrophages from LysM(+);MC4RTB/TB mice compared to LysM(−);MC4RTB/TB mice, which exaggerates with endogenous MC4R ligand treatment; α-MSH. These results suggest that MC4R signaling in macrophages attenuates AAA by inhibiting NF-κB activity and subsequent vascular inflammation.

A central arteriovenous fistula reduces systemic hypertension in a mouse model

“… 40 Although there is some variability in plateauing of blood pressure, this is likely due to measurement techniques and variability in dosage. 41 , 42 Also, the hemodynamic measurements were performed with a non-invasive cuff, allowing serial examinations, but may not correlate with central invasive measurements. Notably, given that the tail artery branch is caudal to the aortocaval fistula, future correlation with invasive central blood pressure measurements will help better characterize these hemodynamic changes.…”

Melanocortins and Their Potential for the Treatment, Prevention and Amelioration of Complications of Diabetes

“…Knocking out MC4R in mice resulted in increased body weight and the development of late-onset hyperglycaemia and atherosclerotic plaque accumulation when fed a semisynthetic diet of 0.02% cholesterol [66]. MC4R knockout mice fed a western diet and infused with ANGII are susceptible to abdominal aortic aneurism, and MC4R mice, on an ApoE ko background, have exacerbated atherosclerosis [67].…”