Mutations in chromatin-modifying complexes and metabolic enzymes commonly underlie complex human developmental syndromes affecting multiple organs. A major challenge is to determine how disease-causing genetic lesions cause deregulation of homeostasis in unique cell types. Here we show that neural-specific depletion of three members of the non-specific lethal (NSL) chromatin complex—Mof, Kansl2 or Kansl3—unexpectedly leads to severe vascular defects and brain haemorrhaging. Deregulation of the epigenetic landscape induced by the loss of the NSL complex in neural cells causes widespread metabolic defects, including an accumulation of free long-chain fatty acids (LCFAs). Free LCFAs induce a Toll-like receptor 4 (TLR4)–NFκB-dependent pro-inflammatory signalling cascade in neighbouring vascular pericytes that is rescued by TLR4 inhibition. Pericytes display functional changes in response to LCFA-induced activation that result in vascular breakdown. Our work establishes that neurovascular function is determined by the neural metabolic environment.

染色质修饰复合物和代谢酶的突变通常是影响多个器官的复杂人类发育综合征的基础。一个主要的挑战是确定致病的遗传损伤如何导致独特细胞类型的体内平衡失调。在这里，我们展示了非特异性致死 (NSL) 染色质复合物的三个成员的神经特异性消耗——Mof、Kansl2或Kansl3——意外导致严重的血管缺损和脑出血。由神经细胞中 NSL 复合物缺失引起的表观遗传景观失调导致广泛的代谢缺陷，包括游离长链脂肪酸 (LCFA) 的积累。游离的 LCFA 在邻近的血管周细胞中诱导 Toll 样受体 4 (TLR4)–NFκB 依赖性促炎信号级联反应，TLR4 抑制可挽救这种级联反应。周细胞响应 LCFA 诱导的激活而表现出功能变化，从而导致血管破裂。我们的工作确定神经血管功能是由神经代谢环境决定的。