IGF1R signaling regulates astrocyte-mediated neurovascular coupling in mice: implications for brain aging

Tarantini, Stefano; Balasubramanian, Priya; Yabluchanskiy, Andriy; Ashpole, Nicole M.; Logan, Sreemathi; Kiss, Tamás; Ungvari, Anna; Nyúl‐Tóth, Ádám; Schwartzman, Michal Laniado; Benyó, Zoltán; Sonntag, William E.; Csiszár, Anna; Ungvári, Zoltán

doi:10.1007/s11357-021-00350-0

Cited by 42 publications

(29 citation statements)

References 86 publications

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“…Several studies suggest that oxidative stress and consequential endothelial dysfunction have a critical role in age-related cerebromicrovascular impairment and neurovascular uncoupling [ 75 , 76 , 77 , 78 , 79 ] in different diseases [ 80 , 81 , 82 , 83 ].…”

Section: Nvu and Its Major Componentsmentioning

confidence: 99%

Oxidative Stress and the Neurovascular Unit

Rinaldi

Donato

Alibrandi

et al. 2021

Life

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The neurovascular unit (NVU) is a relatively recent concept that clearly describes the relationship between brain cells and their blood vessels. The components of the NVU, comprising different types of cells, are so interrelated and associated with each other that they are considered as a single functioning unit. For this reason, even slight disturbances in the NVU could severely affect brain homeostasis and health. In this review, we aim to describe the current state of knowledge concerning the role of oxidative stress on the neurovascular unit and the role of a single cell type in the NVU crosstalk.

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Section: Nvu and Its Major Componentsmentioning

confidence: 99%

Oxidative Stress and the Neurovascular Unit

Rinaldi

Donato

Alibrandi

et al. 2021

Life

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“…These deficits often come as a disconnect from the enhanced longevity observed in animal models of IGF-1 deficiency. While early-life reductions in circulating IGF-1 do lead to increased lifespan, reduced IGF-1 in advanced age has multiple consequences in animal models as it increases sarcopenia, bone frailty, learning and memory deficits, and cerebrovascular dysfunction (Ashpole et al, 2015a;Toth et al, 2015b;Ashpole et al, 2016;Tarantini et al, 2016a;Ashpole et al, 2017;Farias Quipildor et al, 2019;Tarantini et al, 2021). For example, IGF-1 deficiency in mice decreases stimulation-evoked cerebral blood flow, blood brain barrier integrity, and the strength and flexibility of cerebral arteries.…”

Section: Discussionmentioning

confidence: 99%

“…For example, IGF-1 deficiency in mice decreases stimulation-evoked cerebral blood flow, blood brain barrier integrity, and the strength and flexibility of cerebral arteries. IGF-1 deficiency also impairs the production and release of vasomediator eicosanoids from astrocytes, alters endothelial nitric oxide production, and increases susceptibility to hypertension-induced microhemorrhages (Toth et al, 2015b;Tarantini et al, 2017;Fulop et al, 2019;Tarantini et al, 2021). Considering this, it is not surprising that IGF-1 has long-been implicated in the risk and severity of ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted August 9, 2021. ; https://doi.org/10.1101/2021.08.08.455595 doi: bioRxiv preprint also impairs the production and release of vasomediator eicosanoids from astrocytes, alters endothelial nitric oxide production, and increases susceptibility to hypertension-induced microhemorrhages (Toth et al, 2015b;Tarantini et al, 2017;Fulop et al, 2019;Tarantini et al, 2021). Considering this, it is not surprising that IGF-1 has long-been implicated in the risk and severity of ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

“…Animal models of circulating IGF-1 deficiency exhibit impaired neurovascular coupling, compromised blood-brain barrier integrity, and increased prevalence of microhemorrhages (Toth et al, 2015a;Tarantini et al, 2016b;Tarantini et al, 2017;Hayes et al, 2021;Tarantini et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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IGF-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit

Hayes

Ashmore

Vijayasankar

et al. 2021

Preprint

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The age-related reduction in circulating levels of insulin-like growth factor-1 (IGF-1) is associated with increased risk of stroke and neurodegenerative diseases in advanced age. Numerous reports highlight behavioral and physiological deficits in blood-brain barrier function and neurovascular communication when IGF-1 levels are low. Administration of exogenous IGF- 1 reduces the extent of tissue damage and sensorimotor deficits in animal models of ischemic stroke, highlighting the critical role of IGF-1 as a regulator of neurovascular health. The beneficial effects of IGF-1 in the nervous system are often attributed to direct actions on neurons; however, glial cells and the cerebrovasculature are also modulated by IGF-1, and systemic reductions in circulating IGF-1 likely influence the viability and function of the entire neuro-glio-vascular unit. We recently observed that reduced IGF-1 led to impaired glutamate handling in astrocytes. Considering glutamate excitotoxicity is one of the main drivers of neurodegeneration following ischemic stroke, the age-related loss of IGF-1 may also compromise neural function indirectly by altering the function of supporting glia and vasculature. In this study, we assess and compare the effects of IGF-1 signaling on glutamate-induced toxicity and reactive oxygen species (ROS)-produced oxidative stress in primary neuron, astrocyte, and brain microvascular endothelial cell cultures. Our findings verify that neurons are highly susceptible to excitotoxicity, in comparison to astrocytes or endothelial cells, and that a prolonged reduction in IGFR activation increases the extent of toxicity. Moreover, prolonged IGFR inhibition increased the susceptibility of astrocytes to glutamate-induced toxicity and lessened their ability to protect neurons from excitotoxicity. Thus, IGF-1 promotes neuronal survival by acting directly on neurons and indirectly on astrocytes. Despite increased resistance to excitotoxic death, both astrocytes and cerebrovascular endothelial cells exhibit acute increases in glutamate-induced ROS production and mitochondrial dysfunction when IGFR is inhibited at the time of glutamate stimulation. Together these data highlight that each cell type within the neuro-glio-vascular unit differentially responds to stress when IGF-1 signaling was impaired. Therefore, the reductions in circulating IGF-1 observed in advanced age are likely detrimental to the health and function of the entire neuro-glio-vascular unit.

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