Endothelial leptin receptor is dispensable for leptin-induced sympatho-activation and hypertension in male mice.

Leptin plays a crucial role in blood pressure (BP) regulation, notably in the context of obesity through central sympatho-mediated pressor effects. Leptin also relaxes arteries via endothelial (EC) leptin receptor (LepR)-mediated increases in nitric oxide (NO) bioavailability. Herein, we investigated whether leptin-mediated increases in NO bioavailability represent a buffering mechanism against leptin-induced sympatho-activation. We tested the direct contribution of LepR to BP regulation in physiological conditions and in response to chronic leptin infusion using mice deficient in LepR. LepR deficiency did not alter baseline metabolic profile nor leptin-induced reduction in adiposity and increases in energy expenditure. LepR mice demonstrated no increase in baseline BP and heart rate (HR) (MAP: LepR:94.7 ± 1.6, LepR:95.1 ± 1.8 mmHg; HR:LepR:492.4 ± 11.7, LepR:509.5 ± 13.4 bpm) nor in response to leptin (MAP, LepR:101.1 ± 1.7, LepR:101.7 ± 1.8 mmHg; HR, LepR:535.6 ± 11.1, LepR:539.3 ± 14.2 bpm). Moreover, baseline neurogenic control of BP and HR was preserved in LepR mice as well as leptin-mediated increases in sympathetic control of BP and HR and decreases in vagal tone. Remarkably, LepR deficiency did not alter endothelium-dependent relaxation in resistance vessels, nor NO contribution to vasodilatation. Lastly, leptin induced similar increases in adrenergic contractility in mesenteric arteries from both LepR and LepR mice. Collectively, these results demonstrate that the NO buffering effects of leptin are absent in resistance arteries and do not contribute to BP regulation. We provide further evidence that leptin-mediated hypertension involves increased vascular sympatho-activation and extend these findings by demonstrating for the first time that increased cardiac sympatho-activation and reduced vagal tone also contribute to leptin-mediated hypertension.