A PRMT5-ANGPTL4 axis in brain endothelial cells regulates cerebellar inhibitory synaptogenesis and motor coordination.

Brain vasculature is essential for central nervous system function. Here, we found a cerebrovascular signaling axis in which the arginine methyltransferase PRMT5 in endothelial cells promoted proper inhibitory synaptogenesis and motor coordination in male mice. Cerebrovascular endothelial cell-specific deletion of Prmt5 in mice led to excessive inhibitory synaptic input onto Purkinje cells and progressive motor deficits. Mechanistically, Prmt5 deficiency epigenetically increased the expression of the gene encoding the secreted angiocrine ANGPTL4 through reduced symmetric dimethylation of Arg8 in histone H3 and Arg3 in histone H4, which coincided with increased acetylation of Lys9 in histone H3, at the Angptl4 promoter. Angptl4 deletion in brain endothelium normalized inhibitory synaptic input onto Purkinje cells and partially restored motor coordination in mice with a conditional Prmt5 deficiency. Together, these findings define the endothelial PRMT5-ANGPTL4 axis as a key regulator of cerebellar inhibitory circuitry and motor function, highlighting cerebrovascular mechanisms as potential therapeutic targets for motor coordination disorders.