Regulation of vascular angiotensin II type 1 and type 2 receptor and angiotensin-(1-7)/MasR signaling in normal and hypertensive pregnancy

Normal pregnancy (Norm-Preg) is associated with a slight reduction in blood pressure (BP) and decreased BP response to vasoconstrictor stimuli such as angiotensin II (Ang II), although the renin-angiotensin-aldosterone system (RAAS) is upregulated. Preeclampsia (PE) is a complication of pregnancy manifested as hypertension-in-pregnancy (HTN-Preg), and dysregulation of angiotensin biosynthesis and signaling have been implicated. Ang II activates vascular Ang II type-1 receptor (AT₁R) and Ang II type-2 receptor (AT₂R), while angiotensin-(1-7) promotes Ang-(1-7)/MasR signaling. The role of AT₁R in vasoconstriction and the activated cellular mechanisms are well-characterized. The sensitivity of vascular AT₁R to Ang II and consequent activation of vasoconstrictor mechanisms decrease during Norm-Preg, but dramatically increase in HTN-Preg. Placental ischemia in late pregnancy could also initiate the release of AT₁R agonistic autoantibodies (AT₁AA) with significant impact on endothelial dysfunction and activation of contraction pathways in vascular smooth muscle including [Ca²⁺]_c and protein kinase C. On the other hand, the role of AT₂R and Ang-(1-7)/MasR in vascular relaxation, particularly during Norm-Preg and PE, is less clear. During Norm-Preg, increases in the expression/activity of vascular AT₂R and Ang-(1-7)/MasR promote the production of endothelium-derived relaxing factors such as nitric oxide (NO), prostacyclin and endothelium-derived hyperpolarizing factor leading to generalized vasodilation. Aortic segments of Preg rats show prominent endothelial AT₂R staining and increased relaxation and NO production in response to AT₂R agonist CGP42112A, and treatment with AT₂R antagonist PD123319 enhances phenylephrine-induced contraction. Decreased vascular AT₂R and Ang-(1-7)/MasR expression and receptor-mediated mechanisms of vascular relaxation have been suggested in HTN-Preg animal models, but their role in human PE needs further testing. Changes in angiotensin-converting enzyme-2 (ACE2) have been observed in COVID-19 patients, and whether ACE2 influences the course of COVID-19 viral infection/immunity in Norm-Preg and PE is an intriguing area for research.