TY - JOUR
T1 - Reduced endothelial leptin signaling increases vascular adrenergic reactivity in a mouse model of congenital generalized lipodystrophy
AU - Bruder-Nascimento, Thiago
AU - Kress, Taylor C.
AU - Pearson, Matthew
AU - Chen, Weiqin
AU - Kennard, Simone
AU - de Chantemèle, Eric J.Belin
N1 - Funding Information:
Funding: Support for this work has been provided by NIH 1R01HL130301-01, 1R01HL155265-01, 1R01HL147639-01A1 and AHA 19EIA34760167 to E.J.B.d.C. and NIH K99/R00: K99 HL140139-01 and R00 HL140139-03 to T.B.-N.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - The adipokine leptin, which is best-known for its role in the control of metabolic function, is also a master regulator of cardiovascular function. While leptin has been approved for the treatment of metabolic disorders in patients with congenital generalized lipodystrophy (CGL), the effects of chronic leptin deficiency and the treatment on vascular contractility remain unknown. Herein, we investigated the effects of leptin deficiency and treatment (0.3 mg/day/7 days) on aortic contractility in male Berardinelli-Seip 2 gene deficient mice (gBscl2-/-, model of CGL) and their wild-type control (gBscl2+/+ ), as well as in mice with selective deficiency in endothelial leptin receptor (LepREC-/- ). Lipodystrophy selectively increased vascular adrenergic contractility via NO-independent mechanisms and induced hypertrophic vascular remodeling. Leptin treatment and Nox1 inhibition blunted adrenergic hypercontractility in gBscl2-/- mice, however, leptin failed to rescue vascular media thickness. Selective deficiency in endothelial leptin receptor did not alter baseline adrenergic contractility but abolished leptin-mediated reduction in adrenergic contractility, supporting the contribution of endothelium-dependent mechanisms. These data reveal a new direct role for endothelial leptin receptors in the control of vascular contractility and homeostasis, and present leptin as a safe therapy for the treatment of vascular disease in CGL.
AB - The adipokine leptin, which is best-known for its role in the control of metabolic function, is also a master regulator of cardiovascular function. While leptin has been approved for the treatment of metabolic disorders in patients with congenital generalized lipodystrophy (CGL), the effects of chronic leptin deficiency and the treatment on vascular contractility remain unknown. Herein, we investigated the effects of leptin deficiency and treatment (0.3 mg/day/7 days) on aortic contractility in male Berardinelli-Seip 2 gene deficient mice (gBscl2-/-, model of CGL) and their wild-type control (gBscl2+/+ ), as well as in mice with selective deficiency in endothelial leptin receptor (LepREC-/- ). Lipodystrophy selectively increased vascular adrenergic contractility via NO-independent mechanisms and induced hypertrophic vascular remodeling. Leptin treatment and Nox1 inhibition blunted adrenergic hypercontractility in gBscl2-/- mice, however, leptin failed to rescue vascular media thickness. Selective deficiency in endothelial leptin receptor did not alter baseline adrenergic contractility but abolished leptin-mediated reduction in adrenergic contractility, supporting the contribution of endothelium-dependent mechanisms. These data reveal a new direct role for endothelial leptin receptors in the control of vascular contractility and homeostasis, and present leptin as a safe therapy for the treatment of vascular disease in CGL.
KW - Adipose tissue
KW - Leptin
KW - Lipodystrophy
KW - Vascular function
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U2 - 10.3390/ijms221910596
DO - 10.3390/ijms221910596
M3 - Article
C2 - 34638939
AN - SCOPUS:85116001569
SN - 1661-6596
VL - 22
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 19
M1 - 10596
ER -