While the neuronal underpinnings of autism spectrum disorder (ASD) are being unraveled, vascular contributions to ASD remain elusive. Here, we investigated postnatal cerebrovascular development in the 16p11.2^df/+ mouse model of 16p11.2 deletion ASD syndrome. We discover that 16p11.2 hemizygosity leads to male-specific, endothelium-dependent structural and functional neurovascular abnormalities. In 16p11.2^df/+ mice, endothelial dysfunction results in impaired cerebral angiogenesis at postnatal day 14, and in altered neurovascular coupling and cerebrovascular reactivity at postnatal day 50. Moreover, we show that there is defective angiogenesis in primary 16p11.2^df/+ mouse brain endothelial cells and in induced-pluripotent-stem-cell-derived endothelial cells from human carriers of the 16p11.2 deletion. Finally, we find that mice with an endothelium-specific 16p11.2 deletion (16p11.2^ΔEC) partially recapitulate some of the behavioral changes seen in 16p11.2 syndrome, specifically hyperactivity and impaired motor learning. By showing that developmental 16p11.2 haploinsufficiency from endothelial cells results in neurovascular and behavioral changes in adults, our results point to a potential role for endothelial impairment in ASD.

虽然自闭症谱系障碍（ASD）的神经元基础尚不清楚，但血管对ASD的贡献仍然难以捉摸。在这里，我们调查了16p11.2缺失ASD综合征的16p11.2 ^{df / +}小鼠模型中的出生后脑血管发育。我们发现16p11.2半合子导致男性特异性，内皮依赖性结构和功能性神经血管异常。在16p11.2 ^{df / +}小鼠中，内皮功能障碍导致出生后第14天的脑血管生成受损，并在出生后第50天导致神经血管耦合和脑血管反应性改变。此外，我们还显示，原发性16p11.2 ^{df / +}小鼠脑内皮细胞和人多能干细胞衍生的内皮细胞中人载体的16p11.2缺失。最后，我们发现有内皮细胞特异性16p11.2缺失（老鼠16p11.2 ^ΔEC）部分概括一些在16p11.2综合征，特别是多动和受损的运动学习见过的行为变化。通过显示来自内皮细胞的发育性16p11.2单倍体不足会导致成人神经血管和行为的改变，我们的结果表明了ASD中内皮损伤的潜在作用。