Angiotensin II type 1 receptor (AT₁R) autoantibody (AT1‐AA) was first identified as a causative factor in preeclampsia. Unlike physiological ligand angiotensin II (Ang II), AT1‐AA can induce vasoconstriction in a sustained manner, causing a series of adverse effects, such as vascular injury and poor placental perfusion. However, its underlying mechanisms remain unclear. Here, from the perspective of AT₁R internalization, the present study investigated the molecular mechanism of sustained vasoconstriction induced by AT₁R autoantibody.

In the current study, we used the vascular‐ring technique to determine that AT1‐AA‐positive IgG, which was obtained from the sera of preeclamptic patients, induced long‐term vasoconstriction in endothelium‐intact or endothelium‐denuded rat thoracic arteries. The effect was caused by prolonged activation of AT₁R downstream signals in vascular smooth muscle cells, including Ca²⁺, protein kinase C, and extracellular signal‐regulated kinase 1 and 2. Then, using subcellular protein fractionation, cell surface protein biotinylation, and total internal reflection fluorescence, we found that AT1‐AA‐positive IgG resulted in significantly less AT₁R internalization than in the Ang II treatment group. Moreover, through use of fluorescent tracing and bioluminescence resonance energy transfer, we found that AT1‐AA‐positive IgG cannot induce the recruitment of β‐arrestin1/2, which mediated receptor internalization. Then, the effect of sustained AT₁R activation induced by AT1‐AA‐positive IgG was rescued by overexpression of β‐arrestin2.

These data suggested that limited AT₁R internalization resulting from the inhibition of β‐arrestin1/2 recruitment played an important role in sustained vasoconstriction induced by AT1‐AA‐positive IgG, which may set the stage for avoiding AT₁R overactivation in the management of preeclampsia.