Hypertension and Cognitive Dysfunction in a Pregnant Rat Model of PE; a Role for CD4+ T Cells

Preeclampsia (PE) is associated with hypertension (HTN) during pregnancy and activated CD4+ T cells, inflammatory cytokines, and autoantibodies to the angiotensin II type I receptor (AT1-AA). Having had COVID-19 (CV) during pregnancy is associated with an increased incidence of a PE-like phenotype. Both PE and CV have long-lasting neurological implications and studies show that nonpregnant COVID patients produce AT1-AA. We have shown that CD4+ T cells from PE women cause a PE phenotype in nude athymic rats. In this study, we sought to examine the role of CD4+ T cells from PE with a CV History (Hx) to contribute to a PE phenotype and to determine the importance of CD4+ T cells in cognitive dysfunction during pregnancy.

At delivery, blood and placentas were collected, and one million placental CD4+ T cells from each PE and each normotensive patient, with (NT) or without (NP) a CV (Hx) during pregnancy, were isolated, purified, and injected i.p. into a gestational day (GD) 12 pregnant nude athymic rat (one patient/rat). At GD19, blood pressure (MAP) and circulating factors were assessed in recipient rats. Cognitive function and memory were assessed using Novel Object Recognition and Barnes Maze tests, respectively. Placental ACE-2 activity and AT1-AA were measured from COVID Hx patients. A one- or two-way ANOVA with Bonferroni's multiple comparisons test was used for statistical analysis.

Blood pressure was increased in patients with PE, with or without COVID, compared to NT patients. There were no significant changes in placental ACE activity in patients with COVID Hx with or without PE. AT1-AA was elevated in PE patients and in both PE and NT COVID Hx compared to control NP. In pregnant recipient rats, MAP increased in CV Hx PE (113 ± 2, n = 8) compared to CV Hx NT (101 ± 5, n = 6). PE and PE CV Hx CD4+ T Cell recipient rats exhibited impaired memory and cognitive dysfunction (p < 0.05), compared to control groups. Recipient rats of PE CV Hx CD4+ T cells had elevated AT1-AA compared to NT CV Hx recipients. Both COVID Hx groups and recipients of PE CD4+ T cells had elevated TNF alpha compared to NP.

Our findings indicate that pregnant patients with a Hx of COVID during pregnancy produce AT1-AA, with or without PE. Recipients of CD4+ T cells from PE with or without a CV Hx during pregnancy cause HTN and elevated AT1-AA. TNF-α is elevated in PE and in CV Hx NT and PE recipients. Interestingly, recipients of T cells from PE patients with or without a Hx of CV had worse cognitive function during pregnancy, compared to recipient rats of NP CD4+ T cells. These data demonstrate the importance of CD4+ T cells in HTN and impaired neurological function during PE in the presence or absence of a prior COVID-19 infection during pregnancy.