MARRAH ELIZABETH LACHOWICZ-SCROGGINS
$210,490
UNIVERSITY OF MISSISSIPPI MED CTR
Mississippi
National Heart Lung and Blood Institute (NHLBI)
Preeclampsia (PE) affects 12% of deliveries in Mississippi and this incidence of PE increased significantly due to the COVID-19 pandemic rising to 24% in December of 2020. PE is characterized by placental ischemia, inflammation, vascular dysfunction, cognitive decline, hypertension (HTN), IUGR and developmental origins of disease in the offspring. We have shown that agonistic autoantibodies to the angiotensin II type I receptor (AT1- AA) cause placental and cerebral dysfunction contributing to HTN in pregnant rats which is attenuated by blockade of the AT1-AA with the peptide ‘n7AAc’. Moreover, we have shown that the inflammatory cytokine TNF- α stimulates the AT1-AA and causes HTN and cerebral dysfunction during pregnancy. One important unanswered question in PE research is the relative importance of immune mediators to cause HTN and cerebral dysfunction in the pregnant mom or to cause adult HTN in her offspring. Moreover, we don’t know the role of immune mediators as mechanisms of a PE phenotype in pregnant patients with a history (Hx) of COVID 19 infection. Preliminary data in support of AIM 1 are that placental CD4+ T cells cause HTN and cerebrovascular dysfunction in pregnant rats and lead to cognitive dysfunction at 4 months postpartum (PP). Our preliminary data supporting AIM 2 are that Etanercept reduces blood pressure in adoptive transfer recipients of PE T cells. Preliminary data supporting AIM 3 is that HTN, AT1-AA and TNF-α are produced in pregnant women with HTN and a history (Hx) of COVID during pregnancy and in adoptive transfer recipients of T cells from PE women with a COVID 19 Hx during pregnancy compared to recipients of T cells from normotensive women with a Hx of COVID during pregnancy. Based on our findings, we hypothesize that PE stimulated T cells, in the presence or absence of a past COVID infection during pregnancy, secrete TNF-α stimulating B cell secretion of AT1-AA, both of which cause cerebral dysfunction and HTN during pregnancy and programming of cerebral dysfunction and cognitive decline in adult male and female offspring which could be attenuated by either TNF-α or AT1-AA blockade. Specific Aim 1. Does perinatal administration of CD4+T cells from PE women cause HTN and cerebrovascular dysfunction during pregnancy or PP in recipient dams or lead to HTN or cognitive decline in IUGR offspring? Specific Aim 2. Does blockade of AT1-AA or TNF-α in response to perinatal administration of PE CD4+T cells improve HTN and cerebrovascular dysfunction during pregnancy or PP in recipient dams and HTN and cognitive decline in IUGR offspring? Specific Aim 3. Do CD4+T cell mediated inflammatory responses from prior COVID-19 infection lead to PE-like HTN and neurovascular dysfunction in pregnant rats and PP that could be improved with blockade of TNF-α or AT1-AA? Does blockade of AT1-AA or TNF-α in response to perinatal administration of PE CD4+T cells improve HTN and cerebrovascular dysfunction in IUGR offspring?