Phytochemicals from Salvia substolonifera with Anti‐angiogenic Properties and Substolide H Decreased Oxygen‐Induced Retinal Neovascularization

Retinal neovascularization is a pathological feature of ischemic retinopathy. Current therapeutic approaches are limited, and additional treatment options are needed. This study aims to discover lead compounds from Salvia substolonifera that inhibit angiogenesis. As a result, an undescribed norditerpene lactone, substolide H (3), and eight known compounds (1, 2, and 4 ‐ 9) have been isolated. The structure was elucidated using synthetic spectroscopy and electron circular dichroism. Compounds 2, 3, 5, 7, and 9 inhibited HUVEC proliferation with IC50 values of 26.47, 6.10, 43.27, 36.81, and 35.11 μM, respectively. Compounds 2, 3, and 7 inhibited HUVEC migration with IC50 values of 12.48, 8.37, and 7.63 μM, respectively. Further studies have shown that the substolide H (3) suppresses tube formation in HUVECs and that intravitreous administration suppresses retinal neovascularization in OIR mice. Turning to its mechanism of action, we have shown that the anti‐angiogenic effect of the substolide H may be through the downregulation of VEGF expression and the phosphorylation of VEGFR2, ERK1/2, and AKT. Our study represents the first report of these anti‐angiogenic compounds from this plant, and substolide H may be a potential candidate for the treatment of retinal neovascularization.