Vascular Endothelial Regulation of Obesity-Associated Insulin Resistance

Li, Manna; Qian, Ming; Xu, Jian

doi:10.3389/fcvm.2017.00051

Cited by 22 publications

(19 citation statements)

References 127 publications

(135 reference statements)

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“…Obesity is linked to the onset of several cardiovascular diseases and metabolic complications such as hypertension, atherosclerosis, and Type‐2 diabetes (Li et al. ). In addition, obesity is also linked to the aging process, as a major proportion of aged individuals are obese (Bailey‐Downs et al.…”

Section: Introductionmentioning

confidence: 99%

Decreased EDHF‐mediated relaxation is a major mechanism in endothelial dysfunction in resistance arteries in aged mice on prolonged high‐fat sucrose diet

2017

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High‐fat sucrose (HFS) diet in aged individuals causes severe weight gain (obesity) with much higher risk of cardiovascular diseases such as hypertension or atherosclerosis. Endothelial dysfunction is a major contributor for these vascular disorders. We hypothesize that prolonged ingestion of HFS diet by aged mice would accentuate endothelial dysfunction in the small resistance arteries. Male C57BL/6J mice at 12 weeks of age were divided into four groups and fed either normal chow (NC) or high‐fat sucrose diet (HFS). Young group received NC for 4 months, and high‐fat diet (HFD) for 3 months and 1 month HFS + 10% Sucrose (HFS diet). Aged mice received NC for 12 months. Aged HFS group received HFD for 4 months + 1 month HFD + 10% sucrose + 8 months HFD. Total body weight, plasma blood glucose levels, and glucose tolerance were determined in all groups. Isolated mesenteric arteries were assessed for arterial remodeling, myogenic tone, and vasomotor responses using pressure and wire myography. Both young and aged HFS mice showed impaired glucose tolerance (Y‐NC, 137 ± 8.5 vs. Y‐NC HFS, 228 ± 11.71; A‐NC, 148 ± 6.42 vs. A‐HFS, 225 ± 10.99), as well as hypercholesterolemia (Y‐NC 99.50 ± 6.35 vs. Y‐HFS 220.40 ± 16.34 mg/dL; A‐NC 108.6 ± vs. A‐HFS 279 ± 21.64) and significant weight gain (Y‐NC 32.13 ± 0.8 g vs. Y‐HFS 47.87 ± 2.18 g; A‐NC 33.72 vs. A‐HFS 56.28 ± 3.47 g) compared to both groups of mice on NC. The mesenteric artery from mice with prolonged HFS diet resulted in outward hypertrophic remodeling, increased stiffness, reduced myogenic tone, impaired vasodilation, increased contractility and blunted nitric oxide (NO) and EDH‐mediated relaxations. Ebselen, a peroxinitrite scavenger rescued the endothelium derived relaxing factor (EDHF)‐mediated relaxations. Our findings suggest that prolonged diet‐induced obesity of aged mice can worsen small resistance artery endothelial dysfunction due to decrease in NO and EDHF‐mediated relaxation, but, EDHF‐mediated relaxation is a major contributor to overall endothelial dysfunction.

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Section: Introductionmentioning

confidence: 99%

Decreased EDHF‐mediated relaxation is a major mechanism in endothelial dysfunction in resistance arteries in aged mice on prolonged high‐fat sucrose diet

2017

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“…Inflammation is not observed in BMPER iKO mice. Given that vascular inflammation also disrupts function of metabolic tissues such as liver and WAT [18][19][20] , we examined whether BMPER depletion resulted in an inflammatory response in these tissues. In the liver of BMPER iKO and WT mice, the induction of the inflammatory cytokine IL1β ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Loss of Bone Morphogenetic Protein-binding Endothelial Regulator Causes Insulin Resistance

Mao

Fan

et al. 2020

Preprint

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Accumulating evidence suggests chronic inflammation of metabolic tissues plays a causal role in obesity-induced insulin resistance. Yet, how specific endothelial factors exert impacts in metabolic tissues remains undefined. Bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER) adapts endothelial cells to inflammatory stress in diverse organ microenvironments.Here we demonstrate BMPER is a driver of insulin sensitivity. Inducible knockout (iKO) of BMPER causes hyperinsulinemia, glucose intolerance and insulin resistance without increasing inflammation in metabolic tissues. Interestingly, BMPER can directly activate insulin signaling, which requires its internalization and interaction with Niemann-Pick C1 (NPC1), an integral membrane protein that transports intracellular cholesterol. These results suggest the endocrine function of the vascular endothelium maintains glucose homeostasis. Of potential clinical significance, the delivery of BMPER recombinant protein or its overexpression significantly alleviates insulin resistance and hyperglycemia in high-fat diet (HFD)-fed mice and Lepr db/db (db/db) diabetic mice. We conclude that BMPER exhibits therapeutic potential for the treatment of diabetes.Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia and impaired carbohydrates, lipids and protein metabolism resulting from defects in insulin secretion, insulin action or both. More than 100 million U.S. adults are now living with diabetes or prediabetes, a condition that if not treated often leads to type 2 diabetes mellitus (T2DM) within five years 1 . T2DM is the most common form of DM, accounting for 90% to 95% of all diabetic patients and is expected to increase to 693 million by 2045 2 . T2DM is associated with an increased risk of micro-and macrovascular complications, such as diabetic nephropathy, neuropathy, retinopathy and coronary artery disease, which impose profound impacts on the quality of life and health care resources. Current management of diabetes includes lifestyle intervention, routine blood glucose monitoring and pharmacological therapy. However, high costs, variable efficiency and tolerability are important barriers to the use of these pharmacological treatments.

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“…[ 116,344 ] Vasomodulation is adversely affected by impaired vasodilation (reduced secretion of and hyposensitivity to vasodilators) or impaired vasoconstriction (elevated secretion of and hypersensitivity to vasoconstrictors), leading to reduced blood flow and reduced functional hyperemia in response to exercise, food intake, or increase in local metabolism. [ 344,346 ] This chain of events also correlates with microvascular rarefaction (reduction of blood vessel density), reduced perfusion to peripheral limbs and tissues, and hypoxia, and eventually leads to local ischemia and peripheral vascular disease. [ 31,344,346 ]…”

Section: Modeling Vascular Mechanopathology In Vascularized Microphysmentioning

confidence: 99%

“…[ 344,346 ] This chain of events also correlates with microvascular rarefaction (reduction of blood vessel density), reduced perfusion to peripheral limbs and tissues, and hypoxia, and eventually leads to local ischemia and peripheral vascular disease. [ 31,344,346 ]…”

Section: Modeling Vascular Mechanopathology In Vascularized Microphysmentioning

confidence: 99%

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

Pradhan

Banda

Farino

et al. 2020

Adv Healthcare Materials

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The vascular system is integral for maintaining organ‐specific functions and homeostasis. Dysregulation in vascular architecture and function can lead to various chronic or acute disorders. Investigation of the role of the vascular system in health and disease has been accelerated through the development of tissue‐engineered constructs and microphysiological on‐chip platforms. These in vitro systems permit studies of biochemical regulation of vascular networks and parenchymal tissue and provide mechanistic insights into the biophysical and hemodynamic forces acting in organ‐specific niches. Detailed understanding of these forces and the mechanotransductory pathways involved is necessary to develop preventative and therapeutic strategies targeting the vascular system. This review describes vascular structure and function, the role of hemodynamic forces in maintaining vascular homeostasis, and measurement approaches for cell and tissue level mechanical properties influencing vascular phenomena. State‐of‐the‐art techniques for fabricating in vitro microvascular systems, with varying degrees of biological and engineering complexity, are summarized. Finally, the role of vascular mechanobiology in organ‐specific niches and pathophysiological states, and efforts to recapitulate these events using in vitro microphysiological systems, are explored. It is hoped that this review will help readers appreciate the important, but understudied, role of vascular‐parenchymal mechanotransduction in health and disease toward developing mechanotherapeutics for treatment strategies.

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Vascular Endothelial Regulation of Obesity-Associated Insulin Resistance

Cited by 22 publications

References 127 publications

Decreased EDHF‐mediated relaxation is a major mechanism in endothelial dysfunction in resistance arteries in aged mice on prolonged high‐fat sucrose diet

Decreased EDHF‐mediated relaxation is a major mechanism in endothelial dysfunction in resistance arteries in aged mice on prolonged high‐fat sucrose diet

Loss of Bone Morphogenetic Protein-binding Endothelial Regulator Causes Insulin Resistance

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

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