Local Activation of Angiotensin II Type 2 Receptors Improves Microvascular Endothelial Function in Healthy Women With a History Preeclampsia

Kelsey Schwartz; Diana Jalal; Mark Santillan; Anna Stanhewicz

doi:10.1152/physiol.2024.39.S1.1231

Abstract only Women who had preeclampsia (hxPE) have a >4-fold risk for developing cardiovascular disease (CVD) compared to women who had an uncomplicated pregnancy (hxHC). These women demonstrate attenuated vascular endothelium- and nitric oxide (NO)-dependent dilation, secondary to exaggerated angiotensin (ang) II-mediated constriction, following pregnancy but before the onset of CVD. Despite the known dysregulation of ang II-mediated responses postpartum, the role of vasodilatory ang II type 2 receptors (AT 2 R) in this dysfunction is unknown. We hypothesized that, compared to hxHC, hxPE would have reduced AT 2 R-mediated dilation and reduced AT 2 R expression in primary biopsied endothelial cells. We further hypothesized that endothelium- and NO-dependent dilation would be attenuated in hxPE, and that local AT 2 R activation would improve these responses in hxPE. Nine hxPE (34±7 years, 25±14 months postpartum) and 9 hxHC (35±3 years, 32±12 months postpartum) had 4 intradermal microdialysis fibers placed in the ventral forearm. Sites 1-2 received graded infusions of compound 21 (C21, AT 2 R agonist; 10 −14 -10 −3 mol/L) alone or with L-NAME (NO-synthase inhibitor; 15mM). Sites 3-4 received lactated Ringer’s (control) or 10 −11 M C21 and underwent a standard local heating (LH) protocol (42°C; 0.1°C·s −1 ) to assess endothelium-dependent dilation. After full expression of the LH response, 15mM L-NAME was perfused to assess NO-dependent dilation. Red cell flux was measured over each site with laser-Doppler flowmetry. Cutaneous vascular conductance was calculated (CVC=flux/mean arterial pressure) and normalized to maximum (%CVCmax; 28mM SNP+43°C). AT 2 R protein expression in biopsied venous endothelial cells (n=4/group) was quantified using immunofluorescence. AT 2 R-mediated dilation (31±8 vs. hxHC: 95±25%CVCmax, p=0.01) and the NO-dependent portion of this response (21±9 vs. hxHC: 64±23%, p=0.04) was reduced in hxPE. AT 2 R expression in biopsied endothelial cells was attenuated in hxPE (0.59±0.10 vs. hxHC: 0.79±0.07 arbitrary units; p=0.008). hxPE had attenuated endothelium- (79±7 vs. hxHC: 94±9%CVCmax, p<0.001) and NO-dependent dilation (55±11 vs. hxHC: 71±13%; p=0.01) responses to LH. Local AT 2 R activation augmented endothelium- (92±11%CVCmax vs. control; p=0.02) and NO-dependent (78±12% vs. control; p<0.001) dilation in hxPE but had no effect in hxHC (all p>0.05). These data suggest that reductions in AT 2 R-mediated dilation and expression contribute to attenuated endothelial function after preeclampsia. Furthermore, AT 2 R activation may improve endothelial function through NO-dependent mechanisms in women who have had preeclampsia before the onset of CVD. Internal Funds. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Local Activation of Angiotensin II Type 2 Receptors Improves Microvascular Endothelial Function in Healthy Women With a History Preeclampsia

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