Circulating Factors as Markers and Mediators of Endothelial Cell Dysfunction in Preeclampsia

Abstract

During the past decade a new hypothesis has been formulated that explains many of the disparate findings associated with the pregnancy syndrome preeclampsia. With an increased awareness of the physiological significance of vascular endothelial cell function, the seemingly unrelated signs of hypertension, proteinuria, edema, and hypercoagulability have converged to provide clinical evidence of a unifying pathophysiological mechanism: systemic, maternal endothelial cell dysfunction. Investigators have attempted to test this hypothesis through two approaches. The first approach involves the identification of in vivo markers of vascular endothelial cell injury in women with clinically evident preeclampsia. The second approach focuses on the ability of circulating factors derived from the serum or plasma of patients afflicted with preeclampsia to perturb endothelial cell function in vitro. In this review we summarize the increasingly compelling evidence that maternal vascular endothelial cells are a critical target for toxic humoral activities that precipitate the multifaceted preeclampsia syndrome.

Recent Progress Toward the Understanding of the Pathophysiology of Hypertension During Preeclampsia

“…11,12,17,[23][24][25][26][27][28][29][30][31][32][33] Because NO is an important physiological vasodilator in normal pregnancy, it follows that NO deficiency during preeclampsia has been implicated in the disease process. 18,[23][24][25][26][27][28][29][30][31][32][33] Although numerous studies indicate chronic NOS inhibition in pregnant rats produces hypertension associated with peripheral and renal vasoconstriction, proteinuria, intrauterine growth restriction, and increased fetal morbidity, 11,12,25 it is unclear whether an NO deficiency occurs in women with preeclampsia. Much of the uncertainty in this area of research originates from the difficulty in directly assessing the activity of the NO system in the clinical setting.…”

“…Although some studies have reported no significant changes in circulating levels of ET-1 during moderate forms of preeclampsia, a possible role for ET-1 as a paracrine or autocrine agent in preeclampsia remains worthy of consideration. 11,12,23,46,47 Because ET-1 is released toward the vascular smooth muscle in a paracrine fashion, changes in plasma levels of ET may not reflect its local production. Indeed, this is one of the reasons why it has been difficult to ascertain whether preeclampsia is associated with altered ET production.…”

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“…fibronectin, Von Willebrand factor, endothelin 1, asymmetric dimethyl arginine etc.) to show that endothelial function is impaired in peeclampsia (56). Reduced FMD in second trimester has also been reported to be associated with increased risk of preeclampsia (57).…”

The gonadotropins: Tissue-specific angiogenic factors?

“…In detail, preeclampsia is a multifactorial disease process that most likely involves immune components, inflammation, genetics, cytokines or vascular factors, and contributes significantly to maternal and perinatal morbidity and mortality (Torry et al, 2004). Its aetiology is still unclear, but its manifestation in mid-gestation is regarded as a disorder of early placentation and culminates in generalized maternal endothelial cell dysfunction that is characteric for preeclampsia (Taylor et al, 1998;Roberts, 1998).…”