Abstract
Pregnancy is a physiological condition characterized by a progressive increase of the different components of the renin-angiotensin system (RAS). The physiological consequences of the stimulated RAS in normal pregnancy are incompletely understood, and even less understood is the question of how this system may be altered and contribute to the hypertensive disorders of pregnancy. Findings from our group have provided novel insights into how the RAS may contribute to the physiological condition of pregnancy by showing that pregnancy increases the expression of both the vasodilator heptapeptide of the RAS, angiotensin-(1-7) [Ang-(1-7)], and of a newly cloned angiotensin converting enzyme (ACE) homolog, ACE2, that shows high catalytic efficiency for Ang II metabolism to Ang-(1-7). The discovery of ACE2 adds a new dimension to the complexity of the RAS by providing a new arm that may counter-regulate the activity of the vasoconstrictor component, while amplifying the vasodilator component. The studies reviewed in this article demonstrate that Ang-(1-7) increases in plasma and urine of normal pregnant women. In preeclamptic subjects we showed that plasma Ang-(1-7) was suppressed as compared to the levels found in normal pregnancy. In addition, kidney and urinary levels of Ang-(1-7) were increased in pregnant rats coinciding with the enhanced detection and expression of ACE2. These findings support the concept that in normal pregnancy enhanced ACE2 may counteract the elevation in tissue and circulating Ang II by increasing the rate of conversion to Ang-(1-7). These findings provide a basis for the physiological role of Ang-(1-7) and ACE2 during pregnancy.
Highlights
Pregnancy is a physiological condition characterized by a progressive increase of the different components of the renin-angiotensin system (RAS)
Why does an activation of the RAS not result in hypertension in normal pregnancy? Is the down-regulation of the AT1 receptor sufficient to account for the blood pressure changes? Or are there other components of the RAS that need to be considered? In pursuing this question, we discovered that estrogen shifts the pathways of formation of the angiotensin peptides in a tissue-specific manner, reducing formation of angiotensin II (Ang II) and augmenting the production of angiotensin-(1-7) [Ang-(1-7)] in Sprague Dawley and mRen[2] transgenic rats (20)
angiotensin converting enzyme 2 (ACE2) is insensitive to angiotensin converting enzyme (ACE) inhibitors (36,37), a fact suggesting that ACE2 may act to counter-regulate the activity of the vasoconstrictor components of the RAS
Summary
Pregnancy is a physiological condition characterized by a progressive increase of the different components of the renin-angiotensin system (RAS). In pregnant animals administration of angiotensin converting enzyme (ACE) inhibitors results in a decrease in blood pressure, demonstrating the tonic role of Ang II in blood pressure maintenance during pregnancy (17). Ang-(1-7) was demonstrated to contribute to the anti-hypertensive actions of ACE inhibitors and AT1 receptor antagonists (2931). ACE2 is insensitive to ACE inhibitors (captopril, lisinopril and enalapril) (36,37), a fact suggesting that ACE2 may act to counter-regulate the activity of the vasoconstrictor components of the RAS. In light of these new findings, the question was raised if Ang-(17) and ACE2 could contribute to cardiovascular regulation in pregnancy.
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