Impaired Microvascular Function in Obesity

Jongh, Renate T. de; Serné, Erik H.; IJzerman, Richard G.; Vries, G. de; Stehouwer, Coen D. A.

doi:10.1161/01.cir.0000129772.26647.6f

Cited by 351 publications

(148 citation statements)

References 34 publications

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“…In EC‐MR–intact mice, 12 weeks of HFD‐induced obesity resulted in significant impairment of endothelium‐dependent relaxation only in females, with no effect in males (Figure 1A and 1B). These data suggest that in female mice, as in women,5, 36 there is increased susceptibility to microvessel endothelial dysfunction in the setting of obesity. HFD combined with hPCSK9 DY ‐induced hyperlipidemia was associated with endothelial dysfunction in both male and female mice (Figure 1A and 1B).…”

Section: Resultsmentioning

confidence: 73%

“…Obesity and the associated hyperlipidemia and metabolic dysfunction are well‐known risk factors for CVD 4. One of the earliest vascular consequences of these cardiometabolic risk factors is endothelial dysfunction, characterized by impaired endothelium‐dependent relaxation 5, 6, 7. Impaired vasorelaxation decreases organ perfusion capacity and can contribute to the development of hypertension, another CVD risk factor associated with obesity.…”

Section: Introductionmentioning

confidence: 99%

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Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Davel

Lü

Moss

et al. 2018

JAHA

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BackgroundThe incidence of obesity is rising, particularly among women. Microvascular dysfunction is more common with female sex, obesity, and hyperlipidemia and predicts adverse cardiovascular outcomes, but the molecular mechanisms are unclear. Because obesity is associated with mineralocorticoid receptor (MR) activation, we tested the hypothesis that MR in endothelial cells contribute to sex differences in resistance vessel dysfunction in response to cardiometabolic risk factors.Methods and ResultsMale and female endothelial cell–specific MR knockout mice and MR‐intact littermates were randomized to high‐fat‐diet–induced obesity or obesity with hyperlipidemia induced by adeno‐associated virus–based vector targeting transfer of the mutant stable form (DY mutation) of the human PCSK9 (proprotein convertase subtilisin/kexin type 9) gene and compared with control diet. Female but not male mice were sensitive to obesity‐induced endothelial dysfunction, whereas endothelial function was impaired in obese hyperlipidemic males and females. In males, obesity or hyperlipidemia decreased the nitric oxide component of vasodilation without altering superoxide production or endothelial nitric oxide synthase expression or phosphorylation. Decreased nitric oxide content in obese males was overcome by enhanced endothelium‐derived hyperpolarization–mediated relaxation along with increased SK3 expression. Conversely, in females, endothelium‐derived hyperpolarization was significantly impaired by obesity with lower IK1 expression and by hyperlipidemia with lower IK1 and SK3 expression, loss of H2O2‐mediated vasodilation, and increased superoxide production. Endothelial cell–MR deletion prevented endothelial dysfunction induced by risk factors only in females. Rather than restoring endothelium‐derived hyperpolarization in females, endothelial cell–MR deletion enhanced nitric oxide and prevented hyperlipidemia‐induced oxidative stress.ConclusionsThese data reveal distinct mechanisms driving resistance vessel dysfunction in males versus females and suggest that personalized treatments are needed to prevent the progression of vascular disease in the setting of obesity, depending on both the sex and the metabolic profile of each patient.

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Section: Resultsmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Davel

Lü

Moss

et al. 2018

JAHA

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“…These results are consistent with in vitro evidence showing that insulin stimulates NO release by endothelial cells [33] and with in vivo evidence showing that insulin potentiates acetylcholine-induced vasodilatation in resistance arteries [27] and in both skin [28] and muscle [29] microcirculation. This specific effect, however, appears attenuated in insulinresistant states [34], but we have previously shown that, in these conditions [27], insulin can still improve the vascular response to ACh exploiting its hyperpolarising effect. Alternatively, insulin might lose its positive effect on acetylcholine-mediated vasodilatation, which is mainly dependent on endothelial NO synthase activation, but not the ability to preserve the endothelial cell from the negative consequences of hyperglycaemia, which is known to act mainly through oxidative stress.…”

Section: Discussionmentioning

confidence: 76%

Effects of glucose tolerance on the changes provoked by glucose ingestion in microvascular function

et al. 2008

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Aims/hypothesis Hyperglycaemia and hyperinsulinaemia have opposite effects on endothelium-dependent vasodilatation in microcirculation, but the net effect elicited by glucose ingestion and the separate influence of glucose tolerance are unknown. Methods In participants with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or diabetic glucose tolerance, multiple plasma markers of both oxidative stress and endothelial activation, and forearm vascular responses (plethysmography) to intra-arterial acetylcholine (ACh) and sodium nitroprusside (SNP) infusions were measured before and after glucose ingestion. In another IGT group, we evaluated the time-course of the skin vascular responses (laser Doppler) to ACh and SNP (by iontophoresis) 1, 2 and 3 h into the OGTT; the plasma glucose profile was then reproduced by means of a variable intravenous glucose infusion and the vascular measurements repeated. Results Following oral glucose, plasma antioxidants were reduced by 5% to 10% (p<0.01) in all patient groups. The response to acetylcholine was not affected by glucose ingestion in any group, while the response to SNP was attenuated, particularly in the IGT group. The ACh:SNP ratio was slightly improved therefore in all groups, even in diabetic participants, in whom it was impaired basally. A time-dependent improvement in ACh:SNP ratio was also observed in skin microcirculation following oral glucose; this improvement was blunted when matched hyperglycaemia was coupled with lower hyperinsulinaemia (intravenous glucose). Conclusions/interpretation Regardless of glucose tolerance, oral glucose does not impair endothelium-dependent vasodilatation either in resistance arteries or in the microcirculation, despite causing increased oxidative stress; the endogenous insulin response is probably responsible for countering any inhibitory effect on vascular function.

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“…Microvascular dysfunction has already been described in OB, 22 first-degree relatives of diabetic 23 and hypertensive patients, 24 polycystic ovary syndrome 25 and type 2 diabetes mellitus 17 using different methods. Our data confirmed that OW/obese, sedentary, non-smoking and normoglycemic …”

Section: Discussionmentioning

confidence: 99%

Microvascular dysfunction: a direct link among BMI, waist circumference and glucose homeostasis in young overweight/obese normoglycemic women?

2009

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Objective: Capillary recruitment is impaired in obesity (OB), possibly worsening glucose and insulin availability to target organs. In this study, we investigated whether functional microvascular parameters were correlated with clinical-anthropometrical data and whether these parameters would influence OB-related metabolic disorders, especially glucose homeostasis, in young overweight (OW)/obese women. Design: Cross-sectional clinical study of microvascular reactivity in young OW/obese women. Subjects and methods: A total of 10 lean (23.1 ± 3.2 years, body mass index (BMI) 22.3 ± 1.6 kg m À2 ) and 42 OW/obese (24.9±3.5 years; BMI 34.5±5.7 (25.7-46.5) kg m À2 ) sedentary non-smoking women were evaluated. Lipid profile, fasting plasma glucose (PG), post-load PG (75 g-2 h), insulin, C-reactive protein, HOMA-IR (homeostasis model assessment for insulin resistance) index and anthropometric variables (weight, BMI, waist and hip circumferences, waist-to-hip ratio and blood pressure (BP)) were determined. Functional microvascular parameters (functional capillary density, red blood cell velocity at baseline and peak (RBCV max ), and time taken to reach RBCV max (TRBCV max ) during post-occlusive reactive hyperemia after 1 min arterial occlusion) were evaluated by nailfold videocapillaroscopy. Results: The time taken to reach RBCV max was significantly longer in OW/obese patients compared with control subjects (8.6±2.4 versus 5.7±1.1 s, Po0.001), and its delay was directly associated with adiposity levels, systolic BP and insulin resistance, and inversely related to high-density lipoprotein-cholesterol. Post-load PG could be correlated with TRBCV max (R ¼ 0.48, Po0.05) and RBCV max (R ¼ À0.29, Po0.05), and it was influenced by weight, waist circumference and TRBCV max (adjusted R 2 ¼ 24%) as well. Conclusions: In the investigated group of young OW/obese women, the direct correlation between post-load PG and TRBCV max links microvascular parameters with metabolic variables and suggests a key role for microcirculation in OB-related metabolic disorders.

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Impaired Microvascular Function in Obesity

Cited by 351 publications

References 34 publications

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Effects of glucose tolerance on the changes provoked by glucose ingestion in microvascular function

Microvascular dysfunction: a direct link among BMI, waist circumference and glucose homeostasis in young overweight/obese normoglycemic women?

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