Deficiency of Melanocortin 4 Receptor Promotes Vascular Vulnerability in Mice

Background: Obesity is known as a risk factor of hypertension and abdominal aortic aneurysm (AAA) in humans. Melanocortin 4 receptor (MC4R) is primarily expressed in brain, and mediates most of the anorectic effects of leptin; in humans, deficiency or mutation of MC4R is the most common monogenic form of obesity. However, it remains unknown whether MC4R signaling affects the development of obesity-associated hypertension, vascular vulnerability and aortic aneurysm. Methods and Results: MC4R-knockout (KO) mice fed a high-fat/high-sucrose diet (HF/HS) for 20 weeks displayed obesity and insulin resistance associated with hyperleptinemia compared to HF/HS-fed wild type mice. HF/HS-fed MC4R-KO mice exhibited hypertension, and showed increase of medial thickness and elastic lamina destruction in aortae. In aortae of HF/HS-fed MC4R-KO mice, genes of MCP-1, TNF-α, and F4/80 were markedly upregulated relative to HF/HS-fed wild type mice. Following the administration of angiotensin II (Ang II, 500 ng/kg/min), HF/HS-fed MC4R-KO mice showed significantly lower survival rate and higher incidence of AAA than HF/HS-fed wild type mice, with increased expression of F4/80- and osteopontin-positive cells in aortae. Furthermore, HF/HS-fed ob/ob mice exhibited significantly lower incidence of Ang II-induced AAA with a trend of higher survival rate than HF/HS-fed MC4R-KO mice. Leptin (100 ng/ml) significantly upregulated osteopontin gene expression in primary cultured vascular smooth muscle cells (VSMCs), but not in primary cultured macrophages. Conclusion: Our observation clearly demonstrates that deficiency of melanocortin 4 receptor promotes the development of hypertension, vascular vulnerability, and Ang II-induced AAA in mice. It also suggests that hyperleptinemia caused by central leptin resistance could contribute to the development of these vascular phenotypes in MC4R-KO mice, at least partly via induction of osteopontin in VSMCs. Disclosure K. Mori: None. K. Tsuchiya: None. S. Nakamura: None. Y. Miyachi: None. K. Shiba: None. Y. Ogawa: Research Support; Self; AstraZeneca. Advisory Panel; Self; Gilead Sciences, Inc.. Research Support; Self; Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.. K. Kitamura: None.