Abstract 121: Leptin Restores Endothelial Function, Diminishes Vascular Adrenergic Contractility, but Does Not Alter Arterial Stiffness and Blood Pressure, in a Mouse Model of Congenital Generalized Lipodystrophy

Abstract

Leptin which has been associated with cardiovascular disease in the context of obesity, is the current treatment for the metabolic disorders associated with congenital generalized lipodystrophy (CGL). However, the effects of chronic leptin infusion on vascular function and arterial pressure remain unknown in CGL. Here, we hypothesized that deletion in leptin will alter while leptin infusion will restore cardiovascular function via direct vascular mechanisms in CGL in male Berardinelli-Seip 2 gene deficient mice (gBscl2-/-), a mouse model of CGL. CGL mice exhibited reduced adipose mass and leptin levels (gBscl2+/+: 4.03 ± 0.3 vs gBscl2-/-: 0.38 ± 0.1*, ng/dL *P<0.05), as well as evidence of cardiovascular dysfunction including impaired endothelium-dependent relaxation, increased vascular contractility for phenylephrine (gBscl2+/+: 55.3 ± 1 vs gBscl2-/-: 106.2 ± 2.7*, Emax *P<0.05), augmented pulse wave velocity (PWV) (gBscl2+/+: 259.6 ± 20.4 vs gBscl2-/-: 412.4 ± 2.7*, cm/s *P<0.05), vascular fibrosis and elevated mean arterial pressure (MAP) (gBscl2+/+: 100.7 ± 1.4 vs gBscl2-/-: 109.5 ± 2*, mmHg *P<0.05). Blood vessels from CGL mice exhibit increased Nox1 expression gene expression (3 fold) and reactive oxygen species production. Nox1 inhibition (GKT771 10 -5 M) or PPARγ activator (Pioglitazone 10 -5 M) restored endothelial function. Remarkably, chronic (0.3mg/day/7 days) and acute leptin supplementation restored endothelial function and decreased Nox1 expression and ROS production. Selective genetic ablation of leptin receptors in endothelial cells promoted endothelial dysfunction, via Nox-1 dependent mechanisms. Furthermore, leptin reduced vascular adrenergic contractility, but did not reduce MAP, nor PWV or vascular fibrosis in CGL. In conclusion, leptin restores endothelial function via PPARγ-dependent decreases in Nox1, reduces vascular adrenergic contractility, but does not affect the blood pressure and vascular structure, in gBscl2-/- mice. These data reveal a new direct role of leptin receptors in the control of vascular homeostasis and present leptin as a potential therapy for the treatment of vascular disease associated with low leptin levels.