Activation of angiotensin type 2 receptor attenuates testosterone-induced hypertension and uterine vascular resistance in pregnant rats

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

Automated summary

Preeclampsia and testosterone-induced gestational hypertension models show upregulation of AT(1)R and downregulation of AT(2)R, increasing AT(2)R activity could help restore the balance between AT(1)R and AT(2)R and improve gestational vascular function.