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 ^EC )-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 ^EC to BP regulation in physiological conditions and in response to chronic leptin infusion using mice deficient in LepR ^EC . LepR ^EC deficiency did not alter baseline metabolic profile nor leptin-induced reduction in adiposity and increases in energy expenditure. LepR ^EC-/- mice demonstrated no increase in baseline BP and heart rate (HR) (MAP: LepR ^EC+/+ :94.7 ± 1.6, LepR ^EC-/- :95.1 ± 1.8 mmHg; HR:LepR ^EC+/+ :492.4 ± 11.7, LepR ^EC-/- :509.5 ± 13.4 bpm) nor in response to leptin (MAP, LepR ^EC+/+ :101.1 ± 1.7, LepR ^EC-/- :101.7 ± 1.8 mmHg; HR, LepR ^EC+/+ :535.6 ± 11.1, LepR ^EC-/- :539.3 ± 14.2 bpm). Moreover, baseline neurogenic control of BP and HR was preserved in LepR ^EC-/- mice as well as leptin-mediated increases in sympathetic control of BP and HR and decreases in vagal tone. Remarkably, LepR ^EC 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 ^EC+/+ and LepR ^EC-/- 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.
Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. The authors have nothing to disclose.
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