Microvascular Dysfunction in Obesity: A Potential Mechanism in the Pathogenesis of Obesity-Associated Insulin Resistance and Hypertension

Jonk, Amy M.; Houben, Alfons J.H.M.; Jongh, Renate T. de; Serné, Erik H.; Schaper, Nicolaas C.; Stehouwer, Coen D.A.

doi:10.1152/physiol.00012.2007

Cited by 215 publications

(255 citation statements)

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“…It has been proposed, as in muscle, 32 that FFA elevation impairs insulin-mediated activation of PI3-kinase and increases the production of reactive oxygen species, leading to impairment of nitric oxide production and consequently, altered vasodilation. 15 Microvascular rarefaction is also a hallmark of hypertension; the difference in arterial pressure between MetS and control subjects could contribute to the lower CD in patients with MetS. In addition, increased release of endothelin-1, a major vasoconstrictor substance, is likely.…”

Section: Discussionmentioning

confidence: 99%

“…15 Excess secretion of proinflammatory cytokines, such as tumor necrosis factor-a, and decreased production of anti-inflammatory adipokines, such as adiponectin, may also play a role in small-arterial vasculature dysfunction. 15 In a human endothelial cell model, tumor necrosis factor-a has been shown to reduce the expression of endothelial NO synthase, resulting in decreased NO synthesis 33,34 and increased ET-1 expression. 35 In addition, sympathetic neural activation, resulting in higher vasomotor tone, may also contribute to vasoconstriction.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14] Microcirculatory dysfunction has been proposed to be an additional mechanism relating obesity to CVD, through insulin resistance and hypertension. 15 Reduced capillary blood flow may contribute to the development of insulin resistance in muscle and other organs. 15,16 Cytokines originating in adipose tissue, particularly the visceral fat depot, might contribute to insulin resistance and CVD through their adverse impact on blood flow regulation in the microcirculation.…”

Section: Introductionmentioning

confidence: 99%

“…15 Reduced capillary blood flow may contribute to the development of insulin resistance in muscle and other organs. 15,16 Cytokines originating in adipose tissue, particularly the visceral fat depot, might contribute to insulin resistance and CVD through their adverse impact on blood flow regulation in the microcirculation. It has even been proposed that cytokines from perivascular fat depots may also play a role.…”

Section: Introductionmentioning

confidence: 99%

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Macrovascular and microvascular dysfunction in the metabolic syndrome

et al. 2010

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The metabolic syndrome (MetS) is associated with increased risk of type-2 diabetes and cardiovascular disease (CVD). We hypothesized that both small and large arteries may be impaired in subjects with the MetS, even in the absence of known CVD or diabetes. We compared both skin capillary density (CD) and pulse-wave velocity (PWV) in 36 cases with the MetS with those from 108 age-and gender-matched controls from the SU.VIM.AX-2 cohort. Compared with controls, MetS subjects demonstrated increased PWV (12.2 ± 2.8 vs. 10.7 ± 1.9 m s À1 , P¼0.005) and lower functional CD (83.1 ± 15.7 vs. 89.4 ± 14.2 capillaries per mm 2 , P¼0.03). Functional CD was inversely related to fasting glucose, triglycerides (TGs) and HOMA-IR (all Po0.05). On the other hand, no association was found between CD and BP or with PWV. In multivariate models, the odds ratios (95% confidence interval) for one standard deviation change, for having an impaired PWV (X12 m s À1 , n¼44), were: 1.65 (1.11-2.45) for systolic BP and 1.93 (1.25-2.99) for TG only. For impaired CD (p80 capillaries per mm 2 ), the odds ratios (95% confidence interval) were 1.45 (1.00-2.08) for TG and 1.65 (1.13-2.43) for fasting glucose, only. In conclusion, MetS subjects exhibited evidence of macro-and microcirculatory dysfunction, even in the absence of diabetes and CVD. The common mechanism linking MetS components to CVD risk through small-and large-artery dysfunctions may be mediated through metabolic factors related to insulin resistance, not to increased BP.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Macrovascular and microvascular dysfunction in the metabolic syndrome

et al. 2010

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“…[12][13][14] The progression and persistence of obesity have been associated with a progressive alteration of the function and the structure of the vascular wall, including chronic inflammation, endothelial dysfunction, alteration of vascular tone and reactivity, proliferation of smooth muscle cells, neo-angiogenesis and altered patterns of blood flow regulation with both hypertensive and arteriosclerotic consequences. [15][16][17] Some of the metabolic, endocrinologic and hemodynamic changes associated with obesity and hypertension are partially reversed by BW reduction, which decreases BP in overweight non-obese hypertensive patients. Numerous trials of hypertension treatment have shown that weight loss, whether alone or in combination with antihypertensive drugs, has a beneficial effect on BP control.…”

Section: Introductionmentioning

confidence: 99%

Effect of body weight loss and normalization on blood pressure in overweight non-obese patients with stage 1 hypertension

et al. 2010

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We evaluated the effects of body weight (BW) loss on blood pressure (BP) in overweight non-obese patients with stage 1 hypertension. We enrolled 376 overweight (body mass index (BMI) X25 and o30 kg m À2 ) stage 1 hypertensive patients in this prospective 12-month trial. Each patient received tailored, low caloric dietary advice. After 6 months, patients with a BW reduction o5% were excluded. Body weight, BMI, BP, fasting plasma glucose (FPG), fasting plasma insulin (FPI), leptin (pL), renin and aldosterone levels were evaluated at baseline and after 6 and 12 months. In 222 patients who completed the study, a mean weight reduction of 8.1 kg reduced systolic blood pressure (SBP) by 4.2 mm Hg and diastolic blood pressure (DBP) by 3.3 mm Hg (Po0.05), which was accompanied by a significant decrease in FPI, pL and aldosterone levels (Po0.05). Larger SBP/DBP reductions were observed in 106 patients with normalized BMI (À5/À4.5 mm Hg, Po0.01) compared with the 116 patients who did not become normalized (À3.3/À1.6 mm Hg). The former also presented with greater decreases in FPG, FPI, pL, renin and aldosterone levels. Of the 106 patients who had normalized BMI, 52 also had normalized BP. Clinical and metabolic characteristics of these patients were similar to those of the 56 patients who did not have normalized BP. In overweight, mild hypertensive patients, weight loss was effective in reducing BP and in reversing some endocrinologic alterations associated with being overweight. Half of the patients who had normalized BMI also had normalized BP, which could indicate that these patients essentially did not have a form of hypertension but that these effects were instead secondary to being overweight. Keywords: blood pressure; overweight; weight-loss INTRODUCTION Excessive body weight (BW), in particular abdominal obesity, increases the risk for cardiovascular disease, stroke, type 2 diabetes, hypertension, lipoprotein disorders, osteoarthritis, certain types of cancers and total mortality. 1-5 An escalating epidemic of overweight (body mass index (BMI) X25 and o30 kg m À2 ) and obesity (BMI 430 kg m À2 ), is affecting both industrialized and many developing countries in the world, and constitutes a major public health problem. 4,6,7 In particular, in the United States, the prevalence of obesity was estimated at 32% of the population. Being overweight was even more prevalent, representing 42% of men and 28% of women, of whom 34 and 39%, respectively, had high blood pressure (BP). 8,9 The coexistence of hypertension and excessive BW greatly enhances cardiovascular risk. 2,10 Recent recommendations suggest the use of stratification tables to calculate the percentage of increased cardiovascular risk in patients with hypertension and excess BW or obesity. 11 The mechanisms underlying hypertension in subjects with excessive BW

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Developmental Conditioning of the Vasculature

Clough

2014

Comprehensive Physiology

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There is increasing evidence from epidemiological and experimental animal studies that the early life environment, of which nutrition is a key component, acts through developmental adaptive responses to set the capacity of cardiovascular and metabolic pathways to respond to physiological and pathophysiological challenges in later life. One finding that is consistent to both population studies and animal models is the propensity for such effects to induce endothelial dysfunction throughout the vascular tree, including the microvasculature. Obesity, type 2 diabetes and hypertension are associated with changes in microvascular function affecting multiple tissues and organs. These changes may be detected early, often before the onset of macrovascular disease and the development of end organ damage. Suboptimal maternal nutrition and fetal growth result in reduced microvascular perfusion and functional dilator capacity in the offspring, which together with microvascular rarefaction and remodeling serve to limit capillary recruitment, reduce exchange capacity and increase diffusion distances of metabolic substrates; they also increase local and overall peripheral resistance. This article explores how a developmentally conditioned disadvantageous microvascular phenotype may represent an important and additional risk factor for increased susceptibility to the development of cardio-metabolic disease in adult life and considers the cell signaling pathways associated with microvascular dysfunction that may be "primed" by the maternal environment. As the microvasculature has been shown to be a potential target for early therapeutic and lifestyle intervention, this article also considers evidence for the efficacy of such strategies in humans and in animal models of the developmental origins of health and disease.

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Microvascular Dysfunction in Obesity: A Potential Mechanism in the Pathogenesis of Obesity-Associated Insulin Resistance and Hypertension

Cited by 215 publications

References 132 publications

Macrovascular and microvascular dysfunction in the metabolic syndrome

Macrovascular and microvascular dysfunction in the metabolic syndrome

Effect of body weight loss and normalization on blood pressure in overweight non-obese patients with stage 1 hypertension

Developmental Conditioning of the Vasculature

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