Neuronal GPR81 regulates developmental brain angiogenesis and promotes brain recovery after a hypoxic ischemic insult. Issue 7 (July 2022)

• Record Type: Journal Article
• Authors: Chaudhari, Prabhas; Madaan, Ankush; Rivera, José Carlos; Charfi, Iness; Habelrih, Tiffany; Hou, Xin; Nezhady, Mohammad; Lodygensky, Gregory; Pineyro, Graciela; Muanza, Thierry; Chemtob, Sylvain
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 42:Issue 7(2022)
• Page Start: 1294
• Page End: 1308
• Publication Date: 2022-07
• Subjects: Neonatal hypoxia-ischemia -- GPR81 -- lactate -- neurons -- TSP-1 -- VEGF -- brain microvasculature; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X221077499
• Languages: English
• ISSNs: 0271-678X

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.