Direct Vasoconstrictor Effect of Agonistic Autoantibody to the Angiotensin II Type 1 Receptor (AT1-AA) on the Cerebral Microcirculation

Placental ischemia and hypertension, characteristic features of preeclampsia (PE), are also associated with impaired cerebral blood flow (CBF) autoregulation and cerebral edema. Our recent studies have suggested a role for an agonistic autoantibody to the AT1 receptor (AT1-AA), present in preeclamptic women, in the impaired autoregulation of CBF in PE. AT1-AA is also found in PE women up to eight years postpartum and may be a contributing factor to the increased risk for cerebrovascular diseases in these women. Moreover, we have recently found AT1-AA in the circulation of offspring from PE rat models. We found that autoregulation of CBF was impaired in the reduced uterine perfusion pressure (RUPP) rat model of PE, and this response was attenuated by treatment with Losartan or a seven amino acid sequence peptide, ‘n7AAc’, which blocks the actions of AT1- AA. AT1-AA can induce PE symptoms when infused into normal pregnant rats including elevated blood pressure and vascular dysfunction. CBF autoregulation is also impaired during pregnancy and postpartum in normal pregnant female rats infused with purified AT1-AA during pregnancy or following adoptive transfer of CD4+ T helper cells from PE women. However, it remains to be determined whether the AT1 receptor (AT1-AA) directly affects cerebral microcirculation. In the present study, we examined the concentration-related effects of Ang II and purified AT1-AA on the diameter of the middle cerebral artery and parenchymal arterioles of both male and female rats. There were no significant sex differences in the responses of the MCA or PAs obtained from male and female rats to Ang II or AT1-AA. Ang II constricted the diameter of the MCA and PA over the range from 10-12 to 10-8 M by about 15%. AT1-AA had a similar effect at dilutions of 1:1000, 1:100 and 1:50. The responses to both Ang II and AT1-AA were blocked by the AT1 receptor blocker Losartan. We found that the vasoconstrictor response to Ang II and AT1-AA were additive. Ang II 10-8 M did not block the response to a 1:100 concentration of AT1-AA, nor did a submaximal constrictor dose of AT1-AA block the response to 10-8 M Ang II. These findings establish that AT1-AA directly constricts vascular smooth muscle in the MCA and pericytes along the PA via the AT1 receptor. This further implicates AT1AA as a factor contributing to the long-term elevated risk for cerebrovascular dysfunction in postpartum PE women and their children. This study was supported by NIH grants RO1HL170622 (BL), RF1AG079336 (RJR), F31HD110230 (NC), and P20GM121334 (BL). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.