Neuronal GPR81 regulates developmental brain angiogenesis and promotes brain recovery after a hypoxic ischemic insult

Abstract

Perinatal hypoxic/ischemic (HI) brain injury is a major clinical problem with devastating neurodevelopmental outcomes in neonates. During HI brain injury, dysregulated factor production contributes to microvascular impairment. Glycolysis-derived lactate accumulated during ischemia has been proposed to protect against ischemic injury, but its mechanism of action is poorly understood. Herein, we hypothesize that lactate via its G-protein coupled receptor (GPR81) controls postnatal brain angiogenesis and plays a protective role after HI injury. We show that GPR81 is predominantly expressed in neurons of the cerebral cortex and hippocampus. GPR81-null mice displayed a delay in cerebral microvascular development linked to reduced levels of various major angiogenic factors and augmented expression of anti-angiogenic Thrombospondin-1 (TSP-1) in comparison to their WT littermates. Coherently, lactate stimulation induced an increase in growth factors (VEGF, Ang1 and 2, PDGF) and reduced TSP-1 expression in neurons, which contributed to accelerating angiogenesis. HI injury in GPR81-null animals curtailed vascular density and consequently increased infarct size compared to changes seen in WT mice; conversely intracerebroventricular lactate injection increased vascular density and diminished infarct size in WT but not in GPR81-null mice. Collectively, we show that lactate acting via GPR81 participates in developmental brain angiogenesis, and attenuates HI injury by restoring compromised microvasculature.

Insights into the regulation of podocyte and glomerular function by lactate and its metabolic sensor G‐protein‐coupled receptor 81

“…Additionally, increases in TSP-1 and inflammatory factors were found in the absence of GRP81 in GPR81-null mice (Chaudhari et al, 2022).…”

“…Wang et al, 2012). Additionally, lactate and GPR81 activation led to an increase in VEGF production in the brain (Chaudhari et al, 2022;Hunt et al, 2008).…”

“…Lactate can potentiate angiogenesis and neurogenesis by stimulating VEGF production via activation of the nuclear factor‐κB signaling pathway (J. Zhou et al, 2018). A recent study found that neuronal GPR81 regulated angiogenesis and promoted brain recovery through significant increases in proangiogenic factors, such as VEGF and angiotensin‐2, and a significant decrease in antiangiogenic thrombospondin‐1 (TSP‐1) (Chaudhari et al, 2022). TSP‐1 is produced and secreted by neurons and astrocytes where it plays a major role in vascular and neuronal development (Bornstein, 2009; Christopherson et al, 2005).…”

“…TSP‐1 induces a reduction of VEGF (Bornstein, 2009). Additionally, increases in TSP‐1 and inflammatory factors were found in the absence of GRP81 in GPR81‐null mice (Chaudhari et al, 2022). In summary, GPR81 and lactate regulate vascularization by controlling the proper expression of angiogenic and inflammatory factors in the brain.…”

The Succinate Receptor SUCNR1 Resides at the Endoplasmic Reticulum and Relocates to the Plasma Membrane in Hypoxic Conditions

“…Although several recent pharmacological studies refined our understanding of the mechanism of SUCNR1 activation, insight into its regulation and its downstream cellular partners leading to its broader physiological role is lacking. Notably, in the retina (and brain), SUCNR1 is primarily expressed in the cell body, unlike in HEK 293T and Canine kidneys cells, where it appears to be located at the plasma membrane [ 14 , 22 , 26 , 29 ].…”