Sacha inchi shell extract (SISE), whose main active substance is a polysaccharide, has been reported to have hypotensive effects. Consequently, a novel acidic arabinogalactan, termed SISP, was isolated from SISE, and its efficacy in protecting vascular endothelial cells was investigated. SISP had a molecular weight of 57.51 kDa and was composed mainly of Gal, Rha, Ara, and GalA. The main backbone of SISP was composed of →6)-β-D-Galp-(1→, →3,6)-β-D-Galp-(1→, →2)-α-L-Rhap-(1 → and →4)-α-D-GalAp-(1→, and the side chains were branched at the O-3 position of →3,6)-β-D-Galp-(1 → mainly by [α-L-Araf-(1 → 5)-α-L-Araf-(1 → 5,2)-α-L-Araf-(1→], α-L-Araf-(1 → and β-D-Galp-(1→. Compared with the angiotensin II group, high-dose SISP alleviated endothelial cell dysfunction by increasing the vasodilator nitric oxide level by 30.49 % and decreasing the vasoconstrictor endothelin-1 secretion by 53.66 %. Furthermore, SISP protected vascular endothelial cells by reducing oxidative damage via ROS reduction and SOD activity enhancement, inhibiting endothelial cell migration, and activating the ACE2-Ang (1-7)-MasR-AKT-eNOS-NO pathway. Additionally, molecular docking results revealed that SISP could form 23 hydrogen bonds with the central kinase domain of AKT. Therefore, SISP can be potentially used as a vasodilator for the treatment of cardiovascular diseases associated with endothelial dysfunction.