Reductions in angiotensin II type 2 receptor-mediated vasodilation contribute to increased angiotensin II vasoconstrictor sensitivity in women with preeclampsia history.

Schwartz, Campbell, Jalal, Stanhewicz. Reductions in angiotensin II type 2 receptor-mediated vasodilation contribute to increased angiotensin II vasoconstrictor sensitivity in women with preeclampsia history. Clinical Science (London, England : 1979). 2025 May 22; 139(11):545-58, DOI: 10.1042/CS20245238.

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Abstract:

Women with a history of preeclampsia (hxPE) have a ≥4-fold risk for developing cardiovascular disease (CVD) compared with women who had a healthy pregnancy (hxHC). HxPE have exaggerated vasoconstrictor sensitivity to angiotensin (ang) II after pregnancy, which likely contributes to CVD progression after preeclampsia. Ang II-mediated constriction via ang II type 1 receptors (AT1R) is countered by vasodilatory ang II type 2 receptors (AT2R); however, the extent that reductions in AT2R-mediated responses contribute to exaggerated ang II-mediated constriction after preeclampsia is unknown. We examined the balance of AT1R- and AT2R-mediated responses in hxPE and hxHC (n = 12/group). We hypothesized that 1) attenuated AT2R-mediated dilation would be improved with AT1R inhibition in hxPE, and 2) AT2R inhibition would increase ang II-mediated constriction in hxHC but have no effect in hxPE. We measured cutaneous vascular conductance responses to compound 21 (AT2R agonist; 10-14-10-8mol/L) alone or with losartan (AT1R antagonist; 43µmol/L) to assess AT2R-mediated dilation, and ang II (10-20-10-4mol/L) alone or with PD-123319 (AT2R antagonist; 1µmol/L) to assess the role of AT2R in vasoconstrictor sensitivity to ang II. Reduced AT2R-mediated dilation in hxPE (P = 0.002) was improved with AT1R inhibition (P < 0.001). Vasoconstrictor sensitivity to ang II was greater in hxPE compared with hxHC (P < 0.001). Circulating AT1R agonistic autoantibodies (AT1-AA) were elevated in hxPE (P = 0.015). AT2R inhibition increased the vasoconstrictor response to ang II in hxHC (P < 0.001) but had no effect in hxPE (P = 0.19). These data suggest that hxPE have reduced AT2R-mediated dilation that contributes to increased ang II vasoconstrictor sensitivity after preeclampsia.