Abstract 416: Restoration of Leptin Improves Vascular Compliance and Endothelial Function in Obese Mice Exposed to Intermittent Hypoxia
Introduction: Obesity and sleep apnea contribute to pulmonary vascular stiffness. Evidence suggests that the systemic vasculature is similarly affected. We studied a leptin deficient mouse obesity model (ob/ob) with intermittent hypoxia (IH) as a sleep apnea model. We tested the hypotheses that
vascular compliance and endothelial function are decreased in ob/ob mice;
exposure to IH further impairs vascular health; and
leptin replacement restores vascular compliance toward normal.
Methods and Results: WT, ob/ob, and ob/ob + leptin mice were exposed to IH or room air for 4 weeks, creating 6 groups: WT-air, WT-IH, ob/ob-air, ob/ob-IH, ob/ob+lep-air, ob/ob+lep-IH. Pulse wave velocity (PWV) was measured by Doppler to assess vascular stiffness (n=5–9). Vascular relaxation in response to acetylcholine (ACh) was measured in preconstricted thoracic aortic rings (n=9–17). WT-IH mice had increased vascular stiffness vs WT-air (3.85 ± 0.06 vs 3.42 ± 0.06; p<0.0006). Ob/ob-air mice had increased PWV vs WT-air (5.19 ± 0.05 vs 3.40 ± 0.04; p<0.0001). ob/ob-IH mice had a further elevation in PWV vs ob/ob-air (5.54 ± 0.07 vs 5.19 ± 0.05; p<0.002). Interestingly, ob/ob+lep-IH and ob/ob+lep-air were similar (3.37 ± 0.08; vs 3.36 ± 0.12; p=NS) but showed a dramatic restoration of PWV to WT levels (p<0.0001 vs ob/ob-IA; p=NS vs WT-air). ACh response in WT-IH mice was attenuated vs WT-air (Emax, 67.30 ± 2.46 vs 80.02 ± 2.36; p<0.0001) and in ob/ob-IH mice vs ob/ob-air (63.66 ± 2.14; vs 60.01± 1.85; p<0.0001). Ob/ob+lep-air and ob/ob+lep-IH showed improved responses to Ach vs untreated ob/ob-air and -IH (66.99±1.93 and 61.54±2.71). Response to the endothelial-independent vasodilator sodium nitroprusside was similar in all aortic rings.
Conclusions: We conclude that ob/ob mice have increased vascular stiffness due to impaired endothelial function, and IH increases vascular stiffness in WT and ob/ob mice. Remarkably, leptin repletion in both IH-exposed and control ob/ob mice restores normal vascular compliance and improves endothelial function. Thus, impaired leptin signaling may represent a primary mechanism of IH-induced vascular stiffness. The leptin pathway may represent a target for cardiovascular disease associated with sleep apnea and obesity.