Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1

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

doi:10.1038/ncomms15557

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.

Highlights

Physical exercise can improve brain function and delay neurodegeneration; the initial signal from muscle to brain is unknown
Angiogenesis is stimulated by vascular endothelial growth factor A (VEGFA)[10], which directly enhances neurogenesis and synaptic function[11]; the initial molecular signal that leads to increased cerebral VEGFA in response to exercise has not been determined
We uncover that HCAR1 is highly enriched in leptomeningeal fibroblast-like cells that line and surround the pial blood vessels supplying the brain and in pericyte-like cells on intracerebral microvessels, and that activation of this receptor stimulates cerebral VEGFA levels and angiogenesis, providing an initial link between exercise and brain sustenance

Summary

Introduction

Physical exercise can improve brain function and delay neurodegeneration; the initial signal from muscle to brain is unknown. We measured the levels of VEGFA in wild-type and Hcar[1] knockout mice after exercise or L-lactate treatment.

Results

Conclusion