Vascular smooth muscle specific deletion of the leptin receptor attenuates leptin‐induced vascular dysfunction

Abstract

Obesity is a risk factor for cardiovascular disease and is associated with increased plasma levels of the adipose derived hormone leptin. Vascular smooth muscle cells (VSMC) express leptin receptors (LepR); however, their physiological role is unclear. We hypothesized that leptin, at levels to mimic morbid obesity, impairs vascular function. In order to test this, we used wild type and VSMC‐LepR deficient mice (VSMC‐LepR KO) created with a tamoxifen inducible VSMC specific cre recombinase system to delete the LepR gene. 10–12 week old wild type and VSMC‐LepR KO mice were fed a diet containing tamoxifen (0.5 mg/kg) for six weeks, after which vascular reactivity was studied in isolated carotid arteries using an organ chamber bath. Vessels were incubated with leptin (100 ng/ml) or vehicle (0.1 mM Tris HCl) for 30 minutes. Tamoxifen treatment alone did not alter vascular responses to the endothelial dependent or smooth muscle dependent agonist acetylcholine (ACh) or sodium nitroprusside (SNP), respectively. Leptin impaired ACh (10−6 M) induced relaxation in wild type vessels (28±12% vs 88±12%, p<0.05); however, this impairment was markedly blunted in VSMC‐LepR KO (61±12%, p<0.05). These data show that leptin directly impairs vascular function via a leptin receptor mediated mechanism, suggesting a potential pathogenic role for leptin to increase cardiovascular risk during obesity. HL085907, HL051971, HL088421