Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1

Abstract
Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor.

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References

54

[1]

van Praag, H., Shubert, T., Zhao, C. & Gage, F. H. Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 25, 8680–8685 (2005). 10.1523/jneurosci.1731-05.2005

[2]

Barnes, J. N. Exercise, cognitive function, and aging. Adv. Physiol. Educ. 39, 55–62 (2015). 10.1152/advan.00101.2014

[3]

Paillard, T. Preventive effects of regular physical exercise against cognitive decline and the risk of dementia with age advancement. Sports Med. Open 1, 4 (2015). 10.1186/s40798-015-0016-x

[4]

Ding, Y. H. et al. Cerebral angiogenesis and expression of angiogenic factors in aging rats after exercise. Curr. Neurovasc. Res. 3, 15–23 (2006). 10.2174/156720206775541787

[5]

Wightman, E. L. et al. Dietary nitrate modulates cerebral blood flow parameters and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. Physiol. Behav. 149, 149–158 (2015). 10.1016/j.physbeh.2015.05.035

[6]

Farkas, E., Luiten, P. G. & Bari, F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res. Rev. 54, 162–180 (2007). 10.1016/j.brainresrev.2007.01.003

[7]

De Silva, T. M. & Faraci, F. M. Microvascular dysfunction and cognitive impairment. Cell Mol. Neurobiol. 36, 241–258 (2016). 10.1007/s10571-015-0308-1

[8]

Iturria-Medina, Y., Sotero, R. C., Toussaint, P. J., Mateos-Perez, J. M. & Evans, A. C. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis. Nat. Commun. 7, 11934 (2016). 10.1038/ncomms11934

[9]

Paillard, T., Rolland, Y. & de Souto Barreto, P. Protective effects of physical exercise in Alzheimer's disease and Parkinson's disease: a narrative review. J. Clin. Neurol. 11, 212–219 (2015). 10.3988/jcn.2015.11.3.212

[10]

Ferrara, N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog. Horm. Res. 55, 15–35 discussion 35–16 (2000).

[11]

De Rossi, P. et al. A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior. Mol. Psychiatry 21, 1768–1780 (2016). 10.1038/mp.2015.195

[12]

E, L., Lu, J., Selfridge, J. E., Burns, J. M. & Swerdlow, R. H. Lactate administration reproduces specific brain and liver exercise-related changes. J. Neurochem. 127, 91–100 (2013). 10.1111/jnc.12394

[13]

Porporato, P. E. et al. Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice. Angiogenesis 15, 581–592 (2012). 10.1007/s10456-012-9282-0

[14]

Ruan, G. X. & Kazlauskas, A. Lactate engages receptor tyrosine kinases Axl, Tie2, and vascular endothelial growth factor receptor 2 to activate phosphoinositide 3-kinase/Akt and promote angiogenesis. J. Biol. Chem. 288, 21161–21172 (2013). 10.1074/jbc.m113.474619

[15]

Alvarez, Z. et al. Neurogenesis and vascularization of the damaged brain using a lactate-releasing biomimetic scaffold. Biomaterials 35, 4769–4781 (2014). 10.1016/j.biomaterials.2014.02.051

[16]

Shweiki, D., Itin, A., Soffer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992). 10.1038/359843a0

[17]

Osnes, J. B. & Hermansen, L. Acid-base balance after maximal exercise of short duration. J. Appl. Physiol. 32, 59–63 (1972). 10.1152/jappl.1972.32.1.59

[18]

Lauritzen, K. H. et al. Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb. Cortex 24, 2784–2795 (2014). 10.1093/cercor/bht136

[19]

Ahmed, K. et al. An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metab. 11, 311–319 (2010). 10.1016/j.cmet.2010.02.012

[20]

Rolim, N. et al. Aerobic interval training reduces inducible ventricular arrhythmias in diabetic mice after myocardial infarction. Basic Res. Cardiol. 110, 44 (2015). 10.1007/s00395-015-0502-9

[21]

Pitts, F. N. Jr & McClure, J. N. Jr Lactate metabolism in anxiety neurosis. N. Engl. J. Med. 277, 1329–1336 (1967). 10.1056/nejm196712212772502

[22]

Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior

J. Tiago Gonçalves, Simon T. Schafer, Fred H. Gage

Cell 2016 10.1016/j.cell.2016.10.021

[23]

Winkler, E. A., Bell, R. D. & Zlokovic, B. V. Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling. Mol. Neurodegener. 5, 32 (2010). 10.1186/1750-1326-5-32

[24]

Capillary pericytes regulate cerebral blood flow in health and disease

Catherine N. Hall, Clare Reynell, Bodil Gesslein et al.

Nature 2014 10.1038/nature13165

[25]

Stapor, P. C., Sweat, R. S., Dashti, D. C., Betancourt, A. M. & Murfee, W. L. Pericyte dynamics during angiogenesis: new insights from new identities. J. Vasc. Res. 51, 163–174 (2014). 10.1159/000362276

[26]

Dalkara, T. & Alarcon-Martinez, L. Cerebral microvascular pericytes and neurogliovascular signaling in health and disease. Brain Res. 1623, 3–17 (2015). 10.1016/j.brainres.2015.03.047

[27]

Yamanishi, S., Katsumura, K., Kobayashi, T. & Puro, D. G. Extracellular lactate as a dynamic vasoactive signal in the rat retinal microvasculature. Am. J. Physiol. Heart Circ. Physiol. 290, H925–H934 (2006). 10.1152/ajpheart.01012.2005

[28]

Bakker, E. N. et al. Lymphatic clearance of the brain: perivascular, paravascular and significance for neurodegenerative diseases. Cell Mol. Neurobiol. 36, 181–194 (2016). 10.1007/s10571-015-0273-8

[29]

Jessen, N. A., Munk, A. S., Lundgaard, I. & Nedergaard, M. The glymphatic system: a beginner's guide. Neurochem. Res. 40, 2583–2599 (2015). 10.1007/s11064-015-1581-6

[30]

Cai, T. Q. et al. Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem. Biophys. Res. Commun. 377, 987–991 (2008). 10.1016/j.bbrc.2008.10.088

[31]

Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81

Changlu Liu, JieJun Wu, Jessica Zhu et al.

Journal of Biological Chemistry 2009 10.1074/jbc.m806409200

[32]

Morland, C. et al. The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: expression and action in brain. J. Neurosci. Res. 93, 1045–1055 (2015). 10.1002/jnr.23593

[33]

Masoud, G. N. & Li, W. HIF-1alpha pathway: role, regulation and intervention for cancer therapy. Acta Pharm. Sin. B 5, 378–389 (2015). 10.1016/j.apsb.2015.05.007

[34]

Arany, Z. et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature 451, 1008–1012 (2008). 10.1038/nature06613

[35]

Lopez-Lopez, C., Dietrich, M. O., Metzger, F., Loetscher, H. & Torres-Aleman, I. Disturbed cross talk between insulin-like growth factor I and AMP-activated protein kinase as a possible cause of vascular dysfunction in the amyloid precursor protein/presenilin 2 mouse model of Alzheimer's disease. J. Neurosci. 27, 824–831 (2007). 10.1523/jneurosci.4345-06.2007

[36]

Ooi, G. T. et al. Different tissue distribution and hormonal regulation of messenger RNAs encoding rat insulin-like growth factor-binding proteins−1 and −2. Mol. Endocrinol. 4, 321–328 (1990). 10.1210/mend-4-2-321

[37]

Li, G., Wang, H. Q., Wang, L. H., Chen, R. P. & Liu, J. P. Distinct pathways of ERK1/2 activation by hydroxy-carboxylic acid receptor-1. PLoS ONE 9, e93041 (2014). 10.1371/journal.pone.0093041

[38]

Hoque, R., Farooq, A., Ghani, A., Gorelick, F. & Mehal, W. Z. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology 146, 1763–1774 (2014). 10.1053/j.gastro.2014.03.014

[39]

Wang, L. et al. Neural progenitor cells treated with EPO induce angiogenesis through the production of VEGF. J. Cereb. Blood Flow Metab. 28, 1361–1368 (2008). 10.1038/jcbfm.2008.32

[40]

Li, S. & Laher, I. Exercise pills: at the starting line. Trends Pharmacol. Sci. 36, 906–917 (2015). 10.1016/j.tips.2015.08.014

[41]

Muyrers, J. P., Zhang, Y., Testa, G. & Stewart, A. F. Rapid modification of bacterial artificial chromosomes by ET-recombination. Nucleic Acids Res. 27, 1555–1557 (1999). 10.1093/nar/27.6.1555

[42]

Shepherd, J. K., Grewal, S. S., Fletcher, A., Bill, D. J. & Dourish, C. T. Behavioural and pharmacological characterisation of the elevated ‘zero-maze’ as an animal model of anxiety. Psychopharmacology 116, 56–64 (1994). 10.1007/bf02244871

[43]

Walf, A. A. & Frye, C. A. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat. Protoc. 2, 322–328 (2007). 10.1038/nprot.2007.44

[44]

Kemi, O. J., Loennechen, J. P., Wisloff, U. & Ellingsen, O. Intensity-controlled treadmill running in mice: cardiac and skeletal muscle hypertrophy. J. Appl. Physiol. 93, 1301–1309 (2002). 10.1152/japplphysiol.00231.2002

[45]

Running speed and maximal oxygen uptake in rats and mice: practical implications for exercise training

Morten A. Høydal, Ulrik Wisløff, Ole J. Kemi et al.

European Journal of Cardiovascular Prevention &amp... 2007 10.1097/hjr.0b013e3281eacef1

[46]

Wisloff, U., Ellingsen, O. & Kemi, O. J. High-intensity interval training to maximize cardiac benefits of exercise training? Exerc. Sport Sci. Rev. 37, 139–146 (2009). 10.1097/jes.0b013e3181aa65fc

[47]

Desai, K. H. & Bernstein, D. Exercise and oxygen consumption in the mouse. Dev. Cardiovasc. Med. 238, 277–302 (2011). 10.1007/978-1-4615-1653-8_18

[48]

Astles, R., Williams, C. P. & Sedor, F. Stability of plasma lactate in vitro in the presence of antiglycolytic agents. Clin. Chem. 40, 1327–1330 (1994). 10.1093/clinchem/40.7.1327

[49]

West, M. J. Introduction to stereology. Cold Spring Harb. Protoc. 2012, 843–851 (2012).

[50]

Imaging Large-Scale Neural Activity with Cellular Resolution in Awake, Mobile Mice

Daniel A. Dombeck, Anton N. Khabbaz, Forrest Collman et al.

Neuron 2007 10.1016/j.neuron.2007.08.003

Showing 50 of 54 references

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Published: May 23, 2017
Vol/Issue: 8(1)
License: View

Authors

Department of Microbiology, Oslo University Hospital, University of Oslo, Rikshospitalet, 0373 Oslo, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway

Cite This Article

Cecilie Morland, Krister A. Andersson, Øyvind P. Haugen, et al. (2017). Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nature Communications, 8(1). https://doi.org/10.1038/ncomms15557

Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1

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