There is compelling evidence that adaptive changes in the maternal vascular endothelium are important for normal pregnancy and that endothelial dysfunction contributes to the pathogenesis of preeclampsia. The reasons for these changes, however, are not fully understood. Endothelial health/dysfunction ultimately represents a balance between factors that promote injury and the capacity for repair. It has long been thought that repair of the endothelium in the adult occurred solely by adjacent (local) endothelial cell replication, migration, and replacement. New data, however, have demonstrated the presence of endothelial progenitor (precursor) cells (EPCs) that are mobilized from the adult bone marrow into the peripheral circulation upon appropriate stimuli. These cells have the capacity to proliferate, migrate, and differentiate into endothelial cells lining the lumen of blood vessels postnatally. Risk factor-induced dysfunction of EPCs is now thought to contribute to the progression of cardiovascular disease. The long-range hypothesis of the proposed pilot study is that increased mobilization and activity of adult bone marrow-derived EPCs is important for normal pregnancy and that functional impairment of EPCs contributes to development of preeclampsia. Accordingly, Aim la is to test whether the number of EPCs in peripheral blood, and functional activity of EPCs in vitro (survival/proliferation, migration, and integration into vascular structures), increases with pregnancy in the human, correlating with plasma concentrations of estradiol and (free) VEGF and placental growth factor (P1GF).
Aim 1 b is to engineer two fluorescent proteins for tagging endothelial-lineage stem cells in mice using a retroviral vector-based gene delivery technique, and, as an initial experiment, to use these markers to demonstrate that EPCs integrate into the maternal microvasculature.
Aim 2 is to compare women with normal and preeclamptic pregnancies regarding EPC number and function, and to ask if these variables correlate inversely with plasma concentrations of the soluble receptor sFlt-1, an anti-angiogenic circulating antagonist of P1GF and VEGF that is increased in plasma of women with preeclampsia. Building upon data that both cardiovascular morbidity and mortality and cardiovascular risk factors are elevated in women with a history of preeclampsia, Aim 3 is to compare EPCs and plasma factors in women with prior preeclampsia and prior normal pregnancy, 6 to 24 months postpartum. As EPC function is modifiable, this systematic, groundbreaking study could provide clues to prevention or treatment of preeclampsia and associated later-life cardiovascular disease. ? ?
| Bainbridge, Shannon A; Roberts, James M; von Versen-Höynck, Frauke et al. (2009) Uric acid attenuates trophoblast invasion and integration into endothelial cell monolayers. Am J Physiol Cell Physiol 297:C440-50 |
| Lin, Carol; Rajakumar, Augustine; Plymire, Daniel A et al. (2009) Maternal endothelial progenitor colony-forming units with macrophage characteristics are reduced in preeclampsia. Am J Hypertens 22:1014-9 |
| Hubel, Carl A; Powers, Robert W; Snaedal, Sunna et al. (2008) C-reactive protein is elevated 30 years after eclamptic pregnancy. Hypertension 51:1499-505 |
| Gammill, Hilary S; Lin, Carol; Hubel, Carl A (2007) Endothelial progenitor cells and preeclampsia. Front Biosci 12:2383-94 |
| Hubel, Carl A; Wallukat, Gerd; Wolf, Myles et al. (2007) Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia. Hypertension 49:612-7 |
