title: Vascular smooth muscle-specific deletion of the leptin receptor attenuates leptin-induced alterations in vascular relaxation.
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 relaxation. To test this, we used control and VSM-LepR knockout mice (VSM-LepR KO) created with a tamoxifen-inducible specific Cre recombinase to delete the LepR gene in VSMC. Control (10-12 wk old) and VSM-LepR KO (10-12 wk old) mice were fed a diet containing tamoxifen (50 mg/kg) for 6 wk, 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 min. Leptin treatment resulted in significant impairment of vessel relaxation to the endothelial-specific agonist acetylcholine (ACh). When these experiments were repeated in the presence of the superoxide scavenger tempol, relaxation responses to ACh were restored. VSM-LepR deletion resulted in a significant attenuation of leptin-mediated impaired ACh-induced relaxation. These data show that leptin directly impairs vascular relaxation via a VSM-LepR-mediated mechanism, suggesting a potential pathogenic role for leptin to increase cardiovascular risk during obesity.
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, Jackson, Mississippi; and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ryan
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, Jackson, Mississippi; and.
authors.forename: T Taylor
authors.initials: TT
authors.lastname: Coleman
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Sasser
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, Jackson, Mississippi; and.
authors.forename: Katarina M
authors.initials: KM
authors.lastname: Pittman
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, Jackson, Mississippi; and.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hankins
authors.affiliation: Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, Jackson, Mississippi; and dstec@umc.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Stec
mesh_terms: D000818:Animals; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*
chemical_list: D004965:Estrogen Antagonists; D020738:Leptin; D054411:Receptors, Leptin; D013629:Tamoxifen
keywords: Cre recombinase; acetylcholine; endothelial function; hypertension; obesity