The overall goal of this career development proposal is for me to learn, develop and use translational approaches to investigate postpartum neurovascular dysfunction in women with preeclampsia. To achieve this, I will work with a multidisciplinary team of mentors and collaborators including both clinical and basic scientists. Preeclampsia (PEC), a multisystem disorder occurring in 3-8% of pregnancies,1,2 is characterized by hypertension during the second half of pregnancy and widespread endothelial dysfunction. PEC increases the risk of maternal stroke up to 6-fold,1,3 and strokes account for 40-70% of maternal deaths in women with PEC.4,5 Most strokes occur in the first 2 weeks postpartum, often after women have been discharged home.6,7 PEC shares features with the reversible cerebral vasoconstriction syndrome and the posterior reversible encephalopathy syndrome.8,9 These three conditions often overlap in women with postpartum stroke, and are leading causes of ischemic stroke, subarachnoid hemorrhage and intracerebral hemorrhage in this population. We have no biomarkers to predict which women with PEC will develop these devastating complications. The mechanisms by which PEC leads to postpartum stroke are poorly understood. The neurovascular unit, comprising endothelial cells, smooth muscle cells, pericytes, astrocytes, neurons, and extracellular matrix proteins, maintains the structural integrity of the blood-brain barrier. The neurovascular unit also mediates cerebral autoregulation, or the ability of the cerebral vasculature to regulate cerebral blood flow in response to rapid changes in blood pressure. Human and animal studies have implicated abnormalities in both autoregulatory and blood-brain barrier properties of the neurovascular unit in PEC-related cerebrovascular dysfunction.10-15 Animal studies have suggested faulty vascular endothelial growth factor (VEGF) signaling and inflammation may lead to PEC-associated neurovascular unit dysfunction.10,12,16 My central hypothesis is that the neurovascular unit is compromised in peripartum women with severe PEC, due to inflammation and disruptions in VEGF signaling causing both cerebral autoregulatory dysfunction and blood-brain barrier compromise. In the 5-year period of grant support, I will conduct a prospective study in a cohort of 80 pregnant women with and without severe PEC.
In Aim 1, I will use transcranial Doppler and non- invasive blood pressure monitoring to test postpartum cerebral autoregulatory function, correlating the results with levels of VEGF-related proteins and inflammatory cytokines in serum and cerebrospinal fluid collected from study participants at the time of delivery.
In Aim 2, I will expose cultured human brain endothelial cells to the same biospecimens to determine the role of VEGF signaling pathways in PEC-associated blood-brain barrier dysfunction. Through these complementary but independent aims, I hope to identify physiological and serological biomarkers to identify women at higher risk of postpartum acute cerebrovascular complications.
Preeclampsia, a multisystem disorder unique to pregnancy, is associated with increased risk of postpartum stroke. Dysfunction of the neurovascular unit, causing disruption of cerebral autoregulation and blood-brain barrier dysfunction, appears to play an important role in the development of cerebrovascular complications of preeclampsia. I will investigate the effects of preeclampsia on the neurovascular unit in the postpartum period, using both in vivo and in vitro approaches in a cohort of pregnant women with and without severe preeclampsia.
