GPR30 Functions as a Shared Inhibitory Signal for Both Pericyte‐Mediated Angiogenesis and Oligodendrocyte Myelination

ABSTRACT Myelinogenesis is insufficient in numerous myelin‐related diseases in the CNS, leading to functional impairments. Myelinogenesis couples with angiogenesis to ensure adequate need of oxygen and nutrients for oligodendrocyte (OL) differentiation. However, approaches to synchronize myelino‐vascular coupling remain unavailable. We hypothesize the identification of shared signaling pathways in vascular cells and oligodendroglia may yield novel strategies to promote myelin repair through strengthening the blood vessel‐myelination coupling. Here, single‐cell sequencing and in situ hybridization revealed high expression of G‐protein‐coupled receptor 30 ( Gpr30 ) in both vascular cells and oligodendroglia, with selective enrichment in pericytes and oligodendrocyte precursor cells (OPCs). Cell‐specific deletion of GPR30 in pericytes driven by PDGFRβ CreERT2 resulted in enhanced angiogenesis and myelination in developing brains. GPR30 deletion in OPCs or antagonizing GPR30 by G15 resulted in increased MBP‐positive cell density and enhanced nanofiber wrapping capacity in vitro, thereby demonstrating an inhibiting role of GPR30 on OPC differentiation. To elucidate the coordinative role of GPR30 in both cell types, we employed NG2 CreERT to induce a conditional knockout of GPR30 in both NG2‐positive pericytes and OPCs. The conditional deletion of GPR30 enhanced myelination and increased vascular density in developing brains. Further, GPR30 cKO or G15 treatment enhanced myelin repair and functional recovery in the chronic neonatal hypoxia and lysolecithin‐induced demyelination model, suggesting that antagonizing GPR30 is a promising strategy to synchronize angiogenesis with myelination to promote myelinogenesis. These findings establish GPR30 antagonism as a promising approach to enhance myelin repair through synchronizing pericyte‐mediated angiogenesis and OPC differentiation.