Abstract 9071: P-Selectin Glycoprotein Ligand-1 Deficiency is Protective Against Perivascular Macrophage Infiltration and Obesity-Induced Endothelial Dysfunction

Abstract

Introduction: P-selectin glycoprotein ligand-1 (Psgl-1) is a leukocyte ligand which binds to selectins and mediates leukocyte trafficking in several disease states. The goal of the current study was to assess the effects of Psgl-1 deficiency on perivascular adipose tissue (PVAT) macrophage accumulation and endothelial dysfunction in the setting of obesity. Methods: Psgl-1 deficient ( Psgl-1 -/- ) and control ( Psgl-1 +/+ ) mice were fed either normal or DIO chow for 10 weeks (n=5-7 mice per group). Mesenteric arterioles were then mounted on a pressure myograph to evaluate vascular function. Norepinephrine (NE)-induced vasoconstriction, acetylcholine (Ach)-induced (with and without N-nitro-L-arginine methyl ester (L-NAME)) and sodium nitroprusside (SNP)-induced vasorelaxation were evaluated. Mesenteric PVAT macrophage content was assessed with Mac-3 immunohistochemistry. Results: The body weight of DIO mice was greater than standard chow-fed mice (46.5±1.4 vs 21.2±1.6g, p<0.01). NE-induced vasoconstrictions were similar between Psgl-1 +/+ and Psgl-1 -/- mice on DIO or standard chow, however, relaxation responses to Ach were significantly impaired in DIO Psgl-1 +/+ mice compared with standard chow-fed Psgl-1 +/+ mice (maximal relaxation, 36.0±7.8% vs 73.4±5.3%, p<0.01). In contrast Psgl-1 -/- DIO mice were protected from endothelial dysfunction and were similar to Psgl-1 -/- mice on standard chow (maximal relaxation, 75.1±4.8% and 83.8±3.7%). Ach-induced vasorelaxation was completely inhibited in all groups in the presence of L-NAME. Endothelium-independent relaxation responses to SNP were similar in all groups. Mac-3 staining showed reduced macrophage content in mesenteric PVAT of DIO Psgl-1 -/- mice compared to DIO Psgl-1 +/+ mice (18.2±1.5% vs 30.0±2.6% , p<0.01). Treatment of DIO Psgl-1 +/+ mice with a Psgl-1 antibody for 4 weeks resulted in Ach-induced relaxation of 71.6±10.9%, which was similar to Psgl-1 -/- DIO mice. Conclusions: Endothelial function and vascular NO bioavailability are impaired in a DIO mouse model. Psgl-1 deficiency is protective against PVAT inflammation and endothelial dysfunction induced by obesity. Psgl-1 inhibition may be useful for treatment of obesity-related vascular diseases.