Preeclampsia is a pregnancy-related hypertensive disorder with unclear mechanisms. While hypersensitivity to angiotensin II via vasoconstrictive angiotensin type-1 receptor (AT₁R) is observed in preeclampsia, the importance of vasodilatory angiotensin type-2 receptor (AT₂R) in the control of vascular dysfunction is less clear. We assessed whether AT₁R, AT₂R, and endothelial nitric oxide synthase (eNOS) expression are altered in placental vessels of preeclamptic women and tested if ex vivo incubation with AT₂R agonist Compound 21 (C21; 1 µM) could restore AT₁R, AT₂R, and eNOS balance. Further, using a rat model of gestational hypertension induced by elevated testosterone, we examined whether C21 (1 µg/kg/day, oral) could preserve AT₁R and AT₂R balance and improve blood pressure, uterine artery blood flow, and vascular function. Western blots revealed that AT₁R protein level was higher while AT₂R and eNOS protein were reduced in preeclamptic placental vessels, and AT₂R agonist C21 decreased AT₁R and increased AT₂R and eNOS protein levels in preeclamptic vessels. In testosterone dams, blood pressure was higher, and uterine artery blood flow was reduced, and C21 treatment reversed these levels similar to those in controls dams. C21 attenuated the exaggerated Ang II contraction and improved endothelium-dependent vasorelaxation in uterine arteries of testosterone dams. These C21-mediated vascular effects were associated with decreased AT₁R and increased AT₂R and eNOS protein levels. C21 also increased serum nitrate/nitrite and bradykinin production in testosterone dams and attenuated the fetoplacental growth restriction. Thus, AT₁R upregulation and AT₂R downregulation are observed in preeclampsia and testosterone model, and increasing AT₂R activity could help restore AT₁R and AT₂R balance and improve gestational vascular function.

Summary sentence

AT₁R/AT₂R balance is tilted toward vasoconstrictive AT₁R in preeclampsia; restoring this balance using AT₂R agonist mitigates vascular dysfunction in hypertensive pregnant rats, providing a new approach in managing gestational vascular dysfunction.