Differential expression of the angiotensin receptors (AT1, AT2, and AT4) in the placental bed of HIV-infected preeclamptic women of African ancestry

Abstract

The Renin-Angiotensin-Aldosterone System (RAAS) is implicated in the pathophysiology of preeclampsia (PE). There is a paucity of data on uteroplacental angiotensin receptors AT1-2 and 4. We evaluated the immunoexpression of AT1R, AT2R, and AT4R within the placental bed of PE vs. normotensive (N) pregnancies stratified by HIV status. Placental bed (PB) biopsies (n = 180) were obtained from N and PE women. Both groups were stratified by HIV status and gestational age into early-and late onset-PE. Immuno-labeling of AT1R, AT2R, and AT4R was quantified using morphometric image analysis. Immunostaining of PB endothelial cells (EC) and smooth muscle cells of spiral arteries (VSMC) displayed an upregulation of AT1R expression compared to the N group (p < 0.0001). Downregulation of AT2R and AT4R expression was observed in PE vs. N group (p = 0.0042 and p < 0.0001), respectively. AT2R immunoexpression declined between HIV+ve and HIV-ve groups, while AT1R and AT4R displayed an increase. An increase in AT1R expression was noted in the EOPE-ve/+ve and LOPE-ve/+ve compared to N-ve/N+ve. In contrast, AT2R and AT4R expression decreased in EOPE-ve/+ve and LOPE-ve/+ve compared to N-ve/N+ve. We demonstrate a significant downregulation of AT2R and AT4R with a concomitant elevated AT1R immunoexpression within PB of HIV-infected PE women. In addition, a decline in AT2R and AT4R with an increase in AT1R immunoexpression in PE, EOPE, and LOPE vs. normotensive pregnancies, irrespective of HIV status. Thus highlighting differential immunoexpression of uteroplacental RAAS receptors based on pregnancy type, HIV status, and gestational age.

Keywords: Angiotensin II-type 1 receptor (AT1R); Angiotensin II-type 2 receptor (AT2R); Angiotensin II-type 4 receptor (AT4R); Preeclampsia; Renin-Angiotensin Aldosterone System (RAAS).

Fig. 1

Micrographs of immunostained spiral arteries in placental bed tissue for AT1R, AT2R and AT4R of normotensive HIV negative (N-ve); normotensive HIV positive (N+ve)-[A,B]; Early-onset PE/HIV negative (EOPE−ve); Early-onset PE/HIV positive (EOPE+ve)-[C,D]; Late-onset PE/HIV negative (LOPE–ve) and Late-onset PE/HIV positive (LOPE+ve)- [E,F] pregnant women. Placental bed tissue sections are immune-labelled with (from left to right) AT1R, AT2R and AT4R, and counterstained with Haematoxylin (H). Representative images of (A and B) of spiral arteries from a normotensive (N) group with complete physiological transformation, characterized by the presence of AT1R, AT2R and AT4R-positive vascular endothelial cells (EC) and trophoblasts. The intramural fibrinoid (pale blue on H-staining) in the vessel wall, and complete absence of intramural smooth muscle cells. C and D Spiral arteries from the early-onset preeclampsia (EOPE) groups with unsuccessful physiological transformation (EC, tunica media of smooth muscle and trophoblasts [AT1R, AT2R and AT4R positive]). E and F Spiral arteries from the late-onset preeclampsia (LOPE) groups with partial physiological transformation (EC, tunica media of smooth muscle and trophoblasts [AT1R, AT2R and AT4R positive] and presents intramural fibrinoid

Fig. 2

Graphs representing morphometric image analysis of immunostained placental bed tissue in normotensive HIV negative (N−ve); normotensive HIV positive (N+ve); Early-onset PE/HIV negative (EOPE−ve); Early-onset PE/HIV positive (EOPE+ve); Late-onset PE/HIV negative (LOPE−ve) and Late-onset PE/HIV positive (LOPE+ve) pregnant women