TY - JOUR
T1 - Endothelial leptin receptor is dispensable for leptin-induced sympatho-activation and hypertension in male mice
AU - Atawia, Reem T.
AU - Faulkner, Jessica L.
AU - Mehta, Vinay
AU - Austin, Andrew
AU - Jordan, Coleton R.
AU - Kennard, Simone
AU - Belin de Chantemèle, Eric J.
N1 - Copyright © 2022 Elsevier Inc. All rights reserved.
PY - 2022/10
Y1 - 2022/10
N2 - 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 (LepREC)-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 LepREC to BP regulation in physiological conditions and in response to chronic leptin infusion using mice deficient in LepREC. LepREC deficiency did not alter baseline metabolic profile nor leptin-induced reduction in adiposity and increases in energy expenditure. LepREC−/− mice demonstrated no increase in baseline BP and heart rate (HR) (MAP: LepREC+/+:94.7 ± 1.6, LepREC−/−:95.1 ± 1.8 mmHg; HR:LepREC+/+:492.4 ± 11.7, LepREC−/−:509.5 ± 13.4 bpm) nor in response to leptin (MAP, LepREC+/+:101.1 ± 1.7, LepREC−/−:101.7 ± 1.8 mmHg; HR, LepREC+/+:535.6 ± 11.1, LepREC−/−:539.3 ± 14.2 bpm). Moreover, baseline neurogenic control of BP and HR was preserved in LepREC−/− mice as well as leptin-mediated increases in sympathetic control of BP and HR and decreases in vagal tone. Remarkably, LepREC 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 LepREC+/+ and LepREC−/− 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.
AB - 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 (LepREC)-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 LepREC to BP regulation in physiological conditions and in response to chronic leptin infusion using mice deficient in LepREC. LepREC deficiency did not alter baseline metabolic profile nor leptin-induced reduction in adiposity and increases in energy expenditure. LepREC−/− mice demonstrated no increase in baseline BP and heart rate (HR) (MAP: LepREC+/+:94.7 ± 1.6, LepREC−/−:95.1 ± 1.8 mmHg; HR:LepREC+/+:492.4 ± 11.7, LepREC−/−:509.5 ± 13.4 bpm) nor in response to leptin (MAP, LepREC+/+:101.1 ± 1.7, LepREC−/−:101.7 ± 1.8 mmHg; HR, LepREC+/+:535.6 ± 11.1, LepREC−/−:539.3 ± 14.2 bpm). Moreover, baseline neurogenic control of BP and HR was preserved in LepREC−/− mice as well as leptin-mediated increases in sympathetic control of BP and HR and decreases in vagal tone. Remarkably, LepREC 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 LepREC+/+ and LepREC−/− 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.
KW - Adrenergic Agents
KW - Animals
KW - Endothelium/metabolism
KW - Hypertension/genetics
KW - Leptin/pharmacology
KW - Male
KW - Mice
KW - Nitric Oxide
KW - Obesity/genetics
KW - Receptors, Leptin/genetics
UR - http://www.scopus.com/inward/record.url?scp=85135803382&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85135803382&partnerID=8YFLogxK
U2 - 10.1016/j.vph.2022.107093
DO - 10.1016/j.vph.2022.107093
M3 - Article
C2 - 35914636
AN - SCOPUS:85135803382
SN - 1537-1891
VL - 146
SP - 107093
JO - Vascular Pharmacology
JF - Vascular Pharmacology
M1 - 107093
ER -