Aging and Sedentarism Decrease Vascularization and VEGF Levels in the Rat Substantia Nigra. Implications for Parkinson's Disease

Villar-Cheda, Begoña; Sousa-Ribeiro, Daniel; Rodríguez‐Pallares, Jannette; Rodríguez‐Pérez, Ana I.; Guerra, María J.; Labandeira‐Garcia, Jose L.

doi:10.1038/jcbfm.2008.127

Cited by 52 publications

(39 citation statements)

References 15 publications

(40 reference statements)

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“…However, Ndubuizu et al (2009) also reported no significant change in basal VEGF message with age in rat brain cortex, and squamous cell carcinoma tumors from young vs. aged mice displayed similar VEGF mRNA levels (Bojovic and Crowe, 2010). VEGF expression might be altered with aging in discrete brain regions not examined here – e.g., the substantia nigra pars compacta (Villar-Cheda, et al, 2009) – and/or detected age-related changes in VEGF gene activity may correspond more so to other neural cell roles (e.g., neuroprotective/neurogenic) rather than angiogenesis. It is tempting to speculate that, in the absence of concurrent elevation of VEGF, the noted age-related increase in hippocampal expression of Ang2 (the natural antagonist for Ang1) might facilitate vessel destabilization and regression, and muted cerebral angiogenesis during normal aging.…”

Section: 0 Discussionmentioning

confidence: 99%

Brain regional angiogenic potential at the neurovascular unit during normal aging

Murugesan

Demarest

Madri

et al. 2012

Neurobiology of Aging

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Given strong regional specialization of the brain, cerebral angiogenesis may be regionally modified during normal aging. To test this hypothesis, expression of a broad cadre of angiogenesis-associated genes was assayed at the neurovascular unit (NVU) in discrete brain regions of young vs. aged mice by laser capture microdissection coupled to quantitative real-time PCR. Complementary quantitative capillary density/branching studies were performed as well. Effects of physical exercise were also assayed to determine if age-related trends could be reversed. Additionally, gene response to hypoxia was probed to highlight age-associated weaknesses in adapting to this angiogenic stress. Aging impacted resting expression of angiogenesis-associated genes at the NVU in a region-dependent manner. Physical exercise reversed some of these age-associated gene trends, as well as positively influenced cerebral capillary density/branching in a region-dependent way. Lastly, hypoxia revealed a weaker angiogenic response in aged brain. These results suggest heterogeneous changes in angiogenic capacity of the brain during normal aging, and imply a therapeutic benefit of physical exercise that acts at the level of the NVU.

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Section: 0 Discussionmentioning

confidence: 99%

Brain regional angiogenic potential at the neurovascular unit during normal aging

Murugesan

Demarest

Madri

et al. 2012

Neurobiology of Aging

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“…This suggests that overactivity of the Ang II/AT1/Nox axis plays a key role in aging-related iron and ferritin increase in the substantia nigra (Garrido-Gil et al, 2013a). The aging-associated upregulation of Ang II/AT1/Nox activity may lead to upregulation of iron storage by microglia and induce a pro-oxidative pro-inflammatory state and higher vulnerability of dopaminergic cells to degeneration with aging (Collier et al, 2007; Villar-Cheda et al, 2009, 2012b). …”

Section: Interactions Between Ras and Other Microglial Polarization Rmentioning

confidence: 99%

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Labandeira‐Garcia

Rodríguez‐Pérez

Garrido‐Gil

et al. 2017

Front. Aging Neurosci.

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191

182

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Microglia can transform into proinflammatory/classically activated (M1) or anti-inflammatory/alternatively activated (M2) phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory) to M2 (immunoregulatory) phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS) on microglial polarization are less known. It is well known that there is a “classical” circulating RAS; however, a second RAS (local or tissue RAS) has been observed in many tissues, including brain. The locally formed angiotensin is involved in local pathological changes of these tissues and modulates immune cells, which are equipped with all the components of the RAS. There are also recent data showing that brain RAS plays a major role in microglial polarization. Level of microglial NADPH-oxidase (Nox) activation is a major regulator of the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes so that Nox activation promotes the proinflammatory and inhibits the immunoregulatory phenotype. Angiotensin II (Ang II), via its type 1 receptor (AT1), is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects. However, these effects are counteracted by a RAS opposite arm constituted by Angiotensin II/AT2 receptor signaling and Angiotensin 1–7/Mas receptor (MasR) signaling. In addition, activation of prorenin-renin receptors may contribute to activation of the proinflammatory phenotype. Aged brains showed upregulation of AT1 and downregulation of AT2 receptor expression, which may contribute to a pro-oxidative pro-inflammatory state and the increase in neuron vulnerability. Several recent studies have shown interactions between the brain RAS and different factors involved in microglial polarization, such as estrogens, Rho kinase (ROCK), insulin-like growth factor-1 (IGF-1), tumor necrosis factor α (TNF)-α, iron, peroxisome proliferator-activated receptor gamma, and toll-like receptors (TLRs). Metabolic reprogramming has recently been involved in the regulation of the neuroinflammatory response. Interestingly, we have recently observed a mitochondrial RAS, which is altered in aged brains. In conclusion, dysregulation of brain RAS plays a major role in aging-related changes and neurodegeneration by exacerbation of oxidative stress (OS) and neuroinflammation, which may be attenuated by pharmacological manipulation of RAS components.

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“…In addition, exercise has been shown to increase both angiogenesis and neurogenesis in regions of the brain. The hippocampal neurogenic response to exercise is thought to be mediated by VEGF expressed within peripheral organs (Fabel et al 2003; Villar-Cheda et al 2009). Thus, which organs increase VEGF expression in response to an acute exercise bout and the gene regulatory mechanisms that control VEGF expression in each organ remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Exercise-induced VEGF transcriptional activation in brain, lung and skeletal muscle

Tang

Xia

Wagner

et al. 2010

Respiratory Physiology & Neurobiology

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Muscle VEGF expression is upregulated by exercise. Whether this VEGF response is regulated by transcription and/or post-transcriptional mechanisms is unknown. Hypoxia may be responsible: myocyte PO2 falls greatly during exercise and VEGF is a hypoxia-responsive gene. Whether exercise induces VEGF expression in other organs important to acute physical activity is also unknown. To address these questions, we created a VEGF/Luciferase reporter mouse and measured VEGF transcription, mRNA and protein responses to a) acute exercise and b) short-term hypoxia (FIO2=0.06) in brain (brainstem, cerebellum, cortex, hippocampus and striatum), muscle, lung, heart and liver. Exercise increased VEGF transcription, mRNA and protein in brain (hippocampus only), lungs and skeletal muscles, but not liver or heart. Hypoxia increased VEGF expression only in brain (cortex, hippocampus and striatum). New transcription appears to be a major exercise-induced regulatory step for increasing VEGF expression in muscle, lung and brain. Hippocampal VEGF expression was the only component of the exercise response recapitulated by hypoxia equivalent to the Everest summit.

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Aging and Sedentarism Decrease Vascularization and VEGF Levels in the Rat Substantia Nigra. Implications for Parkinson's Disease

Cited by 52 publications

References 15 publications

Brain regional angiogenic potential at the neurovascular unit during normal aging

Brain regional angiogenic potential at the neurovascular unit during normal aging

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Exercise-induced VEGF transcriptional activation in brain, lung and skeletal muscle

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