Project III: Innate immunity, Vascular Dysfunction and HTN during Pregnancy

University Of Mississippi Med Ctr, Jackson MS

Investigators

Abstract

PROJECT SUMMARY Women with hypertensive pregnancies have increased immune activation (CD4+ T cell activation, AT1-AA producing B cells, inflammatory cytokines) and increased risk of cardiovascular disease (CVD) and cerebral vascular dysfunction (CBD) later in life. Antigen presenting cells (APCs), including macrophages (Mɸs), modulate innate and adaptive immune responses to the fetus during pregnancy. Recent studies indicate that secretion of cytokines and expression of co-stimulatory proteins from pro-inflammatory (M1) Mɸs mediate a pro-inflammatory immune response in other diseases. Placental ischemia induces increased M1 Mɸs during pregnancy. However, 1) it is not known if M1 Mɸs play a role in causing vascular dysfunction and hypertension (HTN) during pregnancy by inducing oxidative stress, activating B cells to produce agonistic autoantibodies to the angiotensin type 1 receptor (AT1-AA) or polarizing CD4+ T helper (TH) cells into pro-inflammatory effector cells. Furthermore, 2) it has not been determined if M1s persist postpartum (PP) to promote chronic vascular dysfunction leading to increased CVD risk later in life. We hypothesize that placental ischemia induces increased placental M1 Mɸs, which secrete pro-inflammatory cytokines, polarize pro-inflammatory effector CD4+ TH cells and stimulate B cell- mediated AT1-AA production to cause oxidative stress, endothelial activation, renal injury and vascular dysfunction, leading to HTN and fetal growth restriction (FGR) during pregnancy. These M1s persist PP, mediating a decline in systemic and cerebral vascular function causing HTN and cognitive impairment long-term in the mother. To test this hypothesis, we will use a well-established clinically relevant model of PE; Reduced Uterine Perfusion Pressure (RUPP) rat model. We will also employ our novel model utilizing human macrophage adoptive transfer into immunocompromised pregnant rats. We will leverage these models to identity novel mediators of PE pathophysiology and test innovative therapeutic strategies to mitigate progression of PE and the long-term effects on cardiovascular and cerebral vascular health. We will employ physiological and pharmacological approaches complemented with molecular, biochemical, and in vivo techniques to address vertically integrated specific aims. The proposed studies will provide new and important information regarding the pathophysiological mechanisms linking placental ischemia with maternal HTN and FGR during PE, and with long-term CVD risk in the mother after a PE pregnancy. More importantly this study will identify novel therapeutic targets for the treatment of PE.