– Increased vessel density, BBB leakage and VEGF-A release. – Decreased TJ molecules including occludin and claudin-5. – Rodent model of HD revealed increased transcytosis and paracellular transport in brain ECs with TJ imbalance. – mHtt aggregates localized in ECs, smooth muscle cells and perivascular macrophages. – iPSCs-derived HD BMECs show increased angiogenesis, altered barrier properties and impaired Wnt/β-catenin signaling. Here, CLDN5 is linked to Huntington disease.