Reduced Endothelial Leptin Signaling Increases Vascular Adrenergic Reactivity in a Mouse Model of Congenital Generalized Lipodystrophy

Bruder‐Nascimento, Thiago; Kress, Taylor C.; Pearson, Matthew R.; Chen, Weiqin; Kennard, Simone; Chantemèle, Eric J. Belin de

doi:10.3390/ijms221910596

Cited by 8 publications

(5 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, we showed that while T1D and PFKFB3 overexpression selectively increased the expression of Nox1 and its co-activator NoxA1 in ECs, pharmacological and genetic inhibition of Nox1 restored endothelial function. These findings are consistent with previous work by our group and others highlighting a key role for high endothelial Nox1 expression in reduced NO bioavailability and endothelial dysfunction 24,35,36 but also with reports suggesting a link between glycolysis and Nox-derived ROS. 28 Remarkably, we provided evidence supporting a role for lactate, the end product of glycolysis, in Nox1 upregulation.…”

Section: Discussionsupporting

confidence: 93%

Type 1 Diabetes Impairs Endothelium-Dependent Relaxation Via Increasing Endothelial Cell Glycolysis Through Advanced Glycation End Products, PFKFB3, and Nox1-Mediated Mechanisms

Atawia,

Batori,

Jordan

et al. 2023

Hypertension

Self Cite

View full text Add to dashboard Cite

BACKGROUND: Type 1 diabetes (T1D) is a major cause of endothelial dysfunction. Although cellular bioenergetics has been identified as a new regulator of vascular function, whether glycolysis, the primary bioenergetic pathway in endothelial cells (EC), regulates vascular tone and contributes to impaired endothelium-dependent relaxation (EDR) in T1D remains unknown. METHODS: Experiments were conducted in Akita mice with intact or selective deficiency in EC PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3), the main regulator of glycolysis. Seahorse analyzer and myography were employed to measure glycolysis and mitochondrial respiration, and EDR, respectively, in aortic explants. EC PFKFB3 (Ad-PFKFB3) and glycolysis (Ad-GlycoHi) were increased in situ via adenoviral transduction. RESULTS: T1D increased EC glycolysis and elevated EC expression of PFKFB3 and NADPH oxidase Nox1 (NADPH oxidase homolog 1). Functionally, pharmacological and genetic inhibition of PFKFB3 restored EDR in T1D, while in situ aorta EC transduction with Ad-PFKFB3 or Ad-GlycoHi reproduced the impaired EDR associated with T1D. Nox1 inhibition restored EDR in aortic rings from Akita mice, as well as in Ad-PFKFB3-transduced aorta EC and lactate-treated wild-type aortas. T1D increased the expression of the advanced glycation end product precursor methylglyoxal in the aortas. Exposure of the aortas to methylglyoxal impaired EDR, which was prevented by PFKFB3 inhibition. T1D and exposure to methylglyoxal increased EC expression of HIF1α (hypoxia-inducible factor 1α), whose inhibition blunted methylglyoxal-mediated EC PFKFB3 upregulation. CONCLUSIONS: EC bioenergetics, namely glycolysis, is a new regulator of vasomotion and excess glycolysis, a novel mechanism of endothelial dysfunction in T1D. We introduce excess methylglyoxal, HIF1α, and PFKFB3 as major effectors in T1D-mediated increased EC glycolysis.

show abstract

Section: Discussionsupporting

confidence: 93%

Type 1 Diabetes Impairs Endothelium-Dependent Relaxation Via Increasing Endothelial Cell Glycolysis Through Advanced Glycation End Products, PFKFB3, and Nox1-Mediated Mechanisms

Atawia,

Batori,

Jordan

et al. 2023

Hypertension

Self Cite

View full text Add to dashboard Cite

show abstract

“…The mechanism(s) whereby leptin induces endothelial damage in females may be an indirect mechanism involving the renin-angiotensin-aldosterone system (RAAS). Previous studies show that leptin promotes the development of hypertension and endothelial dysfunction in obese males via increased sympathetic activation; however, these sympathetic nervous system mechanisms are not observed in females [18,[37][38][39]. Aldosterone is a critical regulator of blood pressure and vascular tone.…”

Section: Leptin-induced Endothelial Dysfunction Is Sex-dependentmentioning

confidence: 99%

Mechanisms of leptin-induced endothelial dysfunction

Mellott¹,

Faulkner

2022

Current Opinion in Nephrology &Amp; Hypertension

View full text Add to dashboard Cite

Purpose of reviewEndothelial dysfunction is a major risk factor for many cardiovascular diseases, notably hypertension. Obesity increases the risk of endothelial dysfunction in association with increasing production of the adipokine leptin. Preclinical studies have begun to unravel the mechanisms whereby leptin leads to the development of endothelial dysfunction, which are sex-specific. This review will summarize recent findings of mechanisms of leptin-induced endothelial impairment in both male and females and in pregnancy.Recent findingsLeptin receptors are found in high concentrations in the central nervous system (CNS), via which leptin promotes appetite suppression and upregulates sympathetic nervous system activation. However, leptin receptors are expressed in many other tissues, including the vascular endothelial cells and smooth muscle cells. Recent studies in mice with vascular endothelial or smooth muscle-specific knockdown demonstrate that endothelial leptin receptor activation plays a protective role against endothelial dysfunction in male animals, but not necessarily in females. Clinical studies indicate that women may be more sensitive to obesity-associated vascular endothelial dysfunction. Emerging preclinical data indicates that leptin and progesterone increase aldosterone production and endothelial mineralocorticoid receptor activation, respectively. Furthermore, decades of clinical studies indicate that leptin levels increase in the hypertensive pregnancy disorder preeclampsia, which is characterized by systemic endothelial dysfunction. Leptin infusion in mice induces the clinical characteristics of preeclampsia, including endothelial dysfunction.SummaryNovel preclinical data indicate that the mechanisms whereby leptin promotes endothelial dysfunction are sex-specific. Leptin-induced endothelial dysfunction may also play a role in hypertensive pregnancy as well.

show abstract

“…Endothelium intact aortic rings were mounted in a wire myograph (Danysh MyoTechnology) for isometric tension recordings with PowerLab software (AD Instruments) as described [18][19][20][21] . Briefly, rings (2mm) were placed in tissue baths containing warmed (37 °C), aerated (95% O2, 5% CO2) Krebs Henseleit Solution: (in mM: 130 NaCl, 4.7 KCl, 1.17 MgSO4, 0.03 EDTA, 1.6 CaCl 2, 14.9 NaHCO3, 1.18 KH2PO4, and 5.5 glucose) and after 30 min of stabilization, arteries were incubated with KCl (60mM) to test the sample viability.…”

Section: Vascular Reactivitymentioning

confidence: 99%

Suppressed vascular Rho-kinase activation is a protective cardiovascular mechanism in obese female mice

Barbosa

Costa

Awata

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundObesity is the number one cardiovascular risk factor for both men and women and is a complex condition. Although a sex dimorphism on vascular function has already been noted, the underlying processes remain unclear. The Rho-kinase pathway has a unique role in controlling vascular tone, and in obese male mice, hyperactivation of this system results in worsened vascular constriction. We investigated whether female mice exhibit decreased Rho-kinase activation as a protective mechanism in obesity.MethodsWe exposed male and female mice to a high-fat diet (HFD) for 12 weeks. At the end, energy expenditure, glucose tolerance, adipose tissue inflammation, and vascular function were investigated.ResultsMale mice were more sensitive to HFD-induced body weight gain, glucose tolerance, and inflammation than female mice. After establishing obesity, female mice demonstrated increase in energy expenditure, characterized by an increase in heat, whereas male mice did not. Interestingly, obese female mice, but not male, displayed attenuated vascular contractility to different agonists, such difference was blunted by inhibition of Rho-kinase. Finally, aortae from obese female mice, but not male, responded prematurely to Rho-kinase inhibitor, which was accompanied by a suppressed Rho-kinase activation, measured by western blot.ConclusionIn obesity, female mice demonstrate a vascular protective mechanism – suppression of vascular Rho-kinase – to minimize the cardiovascular risk associated with obesity, whereas male mice do not generate any adaptive response. Future investigations can help to understand how Rho-kinase becomes suppressed in female during obesity.

show abstract

Reduced Endothelial Leptin Signaling Increases Vascular Adrenergic Reactivity in a Mouse Model of Congenital Generalized Lipodystrophy

Cited by 8 publications

References 54 publications

Type 1 Diabetes Impairs Endothelium-Dependent Relaxation Via Increasing Endothelial Cell Glycolysis Through Advanced Glycation End Products, PFKFB3, and Nox1-Mediated Mechanisms

Type 1 Diabetes Impairs Endothelium-Dependent Relaxation Via Increasing Endothelial Cell Glycolysis Through Advanced Glycation End Products, PFKFB3, and Nox1-Mediated Mechanisms

Mechanisms of leptin-induced endothelial dysfunction

Suppressed vascular Rho-kinase activation is a protective cardiovascular mechanism in obese female mice

Contact Info

Product

Resources

About