Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1

Morland, Cecilie; Andersson, Krister; Haugen, Øyvind Pernell; Hadzic, Alena; Kleppa, Liv; Gille, Andreas; Rinholm, Johanne Egge; Palibrk, Vuk; Diget, Elisabeth Holm; Kennedy, Lauritz Hagen; Stølen, Tomas; Hennestad, Eivind; Moldestad, Olve; Cai, Yin; Puchades, Maja; Offermanns, Stefan; Vervaeke, Koen; Bjørås, Magnar; Wisløff, Ulrik; Storm‐Mathisen, Jon; Bergersen, Linda Hildegard

doi:10.1038/ncomms15557

Cited by 370 publications

(369 citation statements)

References 54 publications

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“…Morland et al . () subsequently found that VEGF‐A had a pro‐angiogenic effect in both the hippocampus and sensorimotor cortex.…”

Section: Resultsmentioning

confidence: 96%

“…; Morland et al . ). Both studies found that increased plasma lactate levels brought about by both exercise and systemic administration induced a comparable increase in brain vascular endothelial growth factor‐A (VEGF‐A) and their related signaling pathways.…”

Section: Resultsmentioning

confidence: 97%

“…Alongside the findings of Morland et al . (), that repeated exposure to lactate, artificially or through exercise, promotes VEGF expression, it appears that lactate exerts both short‐ and long‐term angiogenetic effects on the cerebral microvascular in via a common mechanism. Such responses are perhaps unsurprising, considering the classical view of lactate being produced during anaerobic glycolysis as a consequence of exercise or hypoxia.…”

Section: Discussionmentioning

confidence: 99%

“…; Morland et al . ). Evidence from our laboratory indicates that lactate is produced as a consequence to differential transport of glucose and oxygen across the blood–brain barrier (Angleys et al .…”

mentioning

confidence: 97%

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The evidence for the physiological effects of lactate on the cerebral microcirculation: a systematic review

Hollyer

Bordoni

Kousholt

et al. 2019

Journal of Neurochemistry

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Lactate's role in the brain is understood as a contributor to brain energy metabolism, but it may also regulate the cerebral microcirculation. The purpose of this systematic review was to evaluate evidence of lactate as a physiological effector within the normal cerebral microcirculation in reports ranging from in vitro experiments to in vivo studies in animals and humans. Following pre‐registration of a review protocol, we systematically searched the PubMed, EMBASE , and Cochrane databases for literature covering themes of ‘lactate’, ‘the brain’, and ‘microcirculation’. Abstracts were screened, and data extracted independently by two individuals. We excluded studies evaluating lactate in disease models. Twenty‐eight papers were identified, 18 of which were in vivo animal experiments (65%), four on human studies (14%), and six on in vitro or ex vivo experiments (21%). Approximately half of the papers identified lactate as an augmenter of the hyperemic response to functional activation by a visual stimulus or as an instigator of hyperemia in a dose‐dependent manner, without external stimulation. The mechanisms are likely to be coupled to NAD + / NADH redox state influencing the production of nitric oxide. Unfortunately, only 38% of these studies demonstrated any control for bias, which makes reliable generalizations of the conclusions insecure. This systematic review identifies that lactate may act as a dose‐dependent regulator of cerebral microcirculation by augmenting the hyperemic response to functional activation below 5 mmol/kg, and by initiating a hyperemic response above 5 mmol/kg. Open Science Badges This article has received a badge for * Pre‐registration * because it made the data publicly available. The data can be accessed at www.radboudumc.nl/getmedia/53625326-d1df-432c-980f-27c7c80d1a90/THollyer_lactate_protocol.aspx . The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/ .

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“…Morland et al . () subsequently found that VEGF‐A had a pro‐angiogenic effect in both the hippocampus and sensorimotor cortex.…”

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

See 2 more Smart Citations

The evidence for the physiological effects of lactate on the cerebral microcirculation: a systematic review

Hollyer

Bordoni

Kousholt

et al. 2019

Journal of Neurochemistry

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“…It is still unknown whether these factors might influence tumor progression, apoptosis, and metastasis. Exercise can also promote angiogenesis and knowing that the blood vessel walls contain a variety of stem cells (perivascular endothelial and mural cells) [134][135][136] and some of these stem cells have recently been show to have an inhibitory effect on cancer cells through unknown mechanisms, the beneficial effect of exercise on cancer development and prevention is maybe related to these blood vessel derived cells.…”

Section: Epigenetic Regulationmentioning

confidence: 99%

Potential Mechanisms behind Physical Exercise vs. Epigenetic Regulation for Preventing Breast Cancer

Dai¹,

Yang²,

Shi³

et al. 2017

JCPCR

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Potential Mechanisms behind Physical Exercise vs. Epigenetic Regulation for Preventing Breast CancerSubmit Manuscript | http://medcraveonline.com recent years, new applications in both diagnosis and treatment have gradually reduced female breast cancer incidence rates [1]. Considering alternative prevention and therapeutic methods, physical exercise has recently been gaining increased attention in the clinic. Regular exercise appears to lower breast cancer risk by about 10-20 percent, which is a considerable impact from a non-pharmacologic intervention with no cost. Thus, the recently emerging field of exercise-oncology research will be expected to not only clarify the mechanisms behind prevention, but also shed light on future treatment for breast cancer. In this current review, we will summarize recent studies on physical exercise with respect to breast cancer, and discuss their relationship and possible underlying mechanisms. Risk factors for breast cancerBreast cancer is the second most common type of cancer and the leading cause of cancer-related death in women worldwide (link: https://www.breastfriends.org). It is a tremendous disease, affecting lifespan and healthspan. The incidence of breast cancer is increasing every year, and an estimated 252,710 new cases of invasive breast cancer are expected to be diagnosed in women in the U.S. in 2017 (link: http://www.breastcancer.org/symptoms/ understand_bc/statistics). Throughout the world, every year more than 400,000 deaths are caused by breast cancer and, out of these diagnosed cases, there are more than 2.8 million breast cancer survivors [2].Generally, there are two aspects of risk factors for breast cancer (see Table1): (1) [68][69][70]. On the other hand, due to genetic susceptibility influences, which are inherited and unchangeable; the non-modifiable factors are not easily controllable risks for breast cancer. Therefore, it is feasible to reduce the risk factors that are not inherited, but can be changed. Among these modifiable risk factors, physical exercise behaviors not only are beneficial for preventing all stages of cancer development [71], but also are helpful to maintain a healthy weight and reduce risks for developing other diseases, such as cardiovascular disease, diabetes, and stroke [72]. Furthermore, physical activity (PA) has been increasingly regarded as the nonpharmacologic intervention for many cancer patients to combat both the physiologic and psychological effects of cancer treatment [73]. A recent World Health Organization (WHO) report shows that physical inactivity remains one of the most important risk factors for total cancer related mortality (responsible for 6% of total deaths) along with overweight and obesity (responsible for another 5%) [74]. AbstractBreast cancer is the most commonly diagnosed cancer and has been the second leading cause of death due to cancer among women worldwide. It is a disease in which malignant (cancer) cells form in the tissues of the breast and become deadly when they metastasize, spreading to oth...

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Nutritional and metabolic signalling through GPCRs

et al. 2022

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Deregulated metabolism is a well-known feature of several challenging diseases, including diabetes, obesity and cancer. Besides their important role as intracellular bioenergetic molecules, dietary nutrients and metabolic intermediates are released in the extracellular environment. As such, they may achieve unconventional roles as hormone-like molecules by activating cell surface G-protein-coupled receptors (GPCRs) that regulate several pathophysiological processes. In this review, we provide an insight into the role of lactate, succinate, fatty acids, amino acids as well as ketogenesis-derived and b-oxidation-derived intermediates as extracellular signalling molecules. Moreover, the mechanisms by which their cognate metabolite-sensing GPCRs integrate nutritional and metabolic signals with specific intracellular pathways will be described. A better comprehension of these aspects is of fundamental importance to identify GPCRs as novel druggable targets.

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Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1

Cited by 370 publications

References 54 publications

The evidence for the physiological effects of lactate on the cerebral microcirculation: a systematic review

The evidence for the physiological effects of lactate on the cerebral microcirculation: a systematic review

Potential Mechanisms behind Physical Exercise vs. Epigenetic Regulation for Preventing Breast Cancer

Nutritional and metabolic signalling through GPCRs

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