Abstract 12952: Endothelial Cell Specific Deletion of mTOR Ameliorates Age-Related Arterial and Metabolic Dysfunction

Islam, Torikul; Hall, Shelby A; Bloom, Samuel I.; Bramwell, R Colton; Dutson, Tavia; Tucker, Jordan R.; Kim, John; Machin, Daniel R.; Donato, Anthony J.; Lesniewski, Lisa A.

doi:10.1161/circ.144.suppl_1.12952

Cited by 3 publications

(5 citation statements)

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“…In contrast, we found that mTOR activation in mouse MVPCs drove transcriptional reprogramming resulting in increased expression of progenitor markers as well as differentiated vascular capillary, venous, and inflammatory endothelial markers. These data support a mechanism for inhibition of mTOR in the endothelium, which improves autophagy, vascular integrity, attenuation of apoptosis, and inflammation (85)(86)(87). The intersection of these pathways represents control of progenitor function as well as energy sensing and metabolism (88).…”

Section: Methodsmentioning

confidence: 57%

Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging

Mason,

Menon,

Schneider

et al. 2023

Journal of Clinical Investigation

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Reactivation and dysregulation of the mTOR signaling pathway are a hallmark of aging and chronic lung disease; however, the impact on microvascular progenitor cells (MVPCs), capillary angiostasis, and tissue homeostasis is unknown. While the existence of an adult lung vascular progenitor has long been hypothesized, these studies show that Abcg2 enriches for a population of angiogenic tissue-resident MVPCs present in both adult mouse and human lungs using functional, lineage, and transcriptomic analyses. These studies link human and mouse MVPC-specific mTORC1 activation to decreased stemness, angiogenic potential, and disruption of p53 and Wnt pathways, with consequent loss of alveolar-capillary structure and function. Following mTOR activation, these MVPCs adapt a unique transcriptome signature and emerge as a venous subpopulation in the angiodiverse microvascular endothelial subclusters. Thus, our findings support a significant role for mTOR in the maintenance of MVPC function and microvascular niche homeostasis as well as a cell-based mechanism driving loss of tissue structure underlying lung aging and the development of emphysema.

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Section: Methodsmentioning

confidence: 57%

Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging

Mason,

Menon,

Schneider

et al. 2023

Journal of Clinical Investigation

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“…We have recently demonstrated that endothelial-specific reduction in mTOR improves age-related arterial and metabolic dysfunction. 13 Others have shown that EC-specific inactivation of a transcription factor, NF-κB, or tumor suppressor, p53, attenuates HF diet–induced metabolic dysfunction. 17,40 Reduction in inflammatory signals prevents obesity-induced impairments in the phosphorylation of Akt and eNOS.…”

Section: Discussionmentioning

confidence: 99%

“…17 In a recent study, we have found that endothelial mTOR (mammalian target of rapamycin) deletion improves arterial and metabolic function in old mice. 13 Together, these studies suggest that endothelial-specific inflammatory mediators can be a target for arterial dysfunction and associated metabolic dysfunction. In a series of studies in the last decade, Arf6 (ADP ribosylation factor 6) has been described as an inflammatory mediator in the vascular endothelium, although its role in arterial and metabolic function remains largely unknown.…”

mentioning

confidence: 97%

“…Recent discoveries identify a host of metabolic or transcriptional regulatory genes in the endothelium that play critical roles in endothelial and metabolic dysfunction. 5,6,13 For example, endothelial-specific deletion of insulin receptor or irs2 (insulin receptor substrate 2) impairs skeletal muscle glucose uptake. 14,15 Evidence exists that EC-specific deletion of the transcription factor FoxO1 (forkhead box O1) increases skeletal muscle vascular density and suppresses obesity-associated metabolic dysfunction.…”

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confidence: 99%

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Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice

Islam,

Cai,

Allen

et al. 2024

ATVB

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BACKGROUND: Much of what we know about insulin resistance is based on studies from metabolically active tissues such as the liver, adipose tissue, and skeletal muscle. Emerging evidence suggests that the vascular endothelium plays a crucial role in systemic insulin resistance; however, the underlying mechanisms remain incompletely understood. Arf6 (ADP ribosylation factor 6) is a small GTPase that plays a critical role in endothelial cell function. Here, we tested the hypothesis that the deletion of endothelial Arf6 will result in systemic insulin resistance. METHODS: We used mouse models of constitutive endothelial cell–specific Arf6 deletion (Arf6 f/ − Tie2Cre) and tamoxifen-inducible Arf6 knockout (Arf6 f/f Cdh5CreER+). Endothelium-dependent vasodilation was assessed using pressure myography. Metabolic function was assessed using a battery of metabolic assessments including glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. We used a fluorescence microsphere–based technique to measure tissue blood flow. Skeletal muscle capillary density was assessed using intravital microscopy. RESULTS: Endothelial Arf6 deletion impaired insulin-stimulated vasodilation in white adipose tissue and skeletal muscle feed arteries. The impairment in vasodilation was primarily due to attenuated insulin-stimulated NO bioavailability but independent of altered acetylcholine-mediated or sodium nitroprusside–mediated vasodilation. Endothelial cell–specific deletion of Arf6 also resulted in systematic insulin resistance in normal chow–fed mice and glucose intolerance in high-fat diet–fed obese mice. The underlying mechanisms of glucose intolerance were reductions in insulin-stimulated blood flow and glucose uptake in the skeletal muscle and were independent of changes in capillary density or vascular permeability. CONCLUSIONS: Results from this study support the conclusion that endothelial Arf6 signaling is essential for maintaining insulin sensitivity. Reduced expression of endothelial Arf6 impairs insulin-mediated vasodilation and results in systemic insulin resistance. These results have therapeutic implications for diseases that are associated with endothelial cell dysfunction and insulin resistance such as diabetes.

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“…30 On the contrary, improvement in endothelium-dependent dilation in old mice lacking mammalian target of rapamycin specifically in endothelial cells was shown to ameliorate glucose and lipid tolerance and attenuate hepatic gluconeogenesis. 31 Dysfunction of sinusoidal endothelial cells in the liver has been implicated in the progression of nonalcoholic fatty liver disease via numerous mechanisms, including dysregulation of the inflammatory process, activation of hepatic stellate cells, augmentation of vascular resistance, and distortion of the microcirculation, resulting in the progression of nonalcoholic fatty liver disease. 32,33…”

Section: Metabolic Impact Of Cardiovascular Organsmentioning

confidence: 99%

Neural Circuits Underlying Reciprocal Cardiometabolic Crosstalk: 2023 Arthur C. Corcoran Memorial Lecture

Rahmouni

2024

Hypertension

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The interplay of various body systems, encompassing those that govern cardiovascular and metabolic functions, has evolved alongside the development of multicellular organisms. This evolutionary process is essential for the coordination and maintenance of homeostasis and overall health by facilitating the adaptation of the organism to internal and external cues. Disruption of these complex interactions contributes to the development and progression of pathologies that involve multiple organs. Obesity-associated cardiovascular risks, such as hypertension, highlight the significant influence that metabolic processes exert on the cardiovascular system. This cardiometabolic communication is reciprocal, as indicated by substantial evidence pointing to the ability of the cardiovascular system to affect metabolic processes, with pathophysiological implications in disease conditions. In this review, I outline the bidirectional nature of the cardiometabolic interaction, with special emphasis on the impact that metabolic organs have on the cardiovascular system. I also discuss the contribution of the neural circuits and autonomic nervous system in mediating the crosstalk between cardiovascular and metabolic functions in health and disease, along with the molecular mechanisms involved.

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Abstract 12952: Endothelial Cell Specific Deletion of mTOR Ameliorates Age-Related Arterial and Metabolic Dysfunction

Cited by 3 publications

References 0 publications

Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging

Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging

Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice

Neural Circuits Underlying Reciprocal Cardiometabolic Crosstalk: 2023 Arthur C. Corcoran Memorial Lecture

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