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Preeclampsia: Pathogenesis and molecular mechanism

Preeclampsia is a pregnancy-specific disorder that affects 3–5% (1, 2) of pregnant women worldwide and is one of the most frequently encountered medical complication of pregnancy. Classically, the condition presents with new onset hypertension and proteinuria after 20 weeks of gestation.


Preeclampsia is a systemic syndrome of pregnancy originating in the placenta. It is thought to be caused by inadequate placental cytotrophoblast invasion, followed by widespread maternal endothelial dysfunction. Research has demonstrated that excess quantities of the antiangiogenic factors soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) are released by the placenta into maternal blood, causing widespread endothelial dysfunction that results in hypertension, proteinuria, and other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown. The role of these antiangiogenic proteins in early placental vascular development and in trophoblast invasion is just beginning to be explored. Hypoxia is likely to be an important regulator. Additionally, perturbation of the renin–aldosterone–angiotensin II axis, excessive oxidative stress, inflammation, immune maladaptation, and genetic susceptibility may all contribute to the pathogenesis of preeclampsia.

Role of placenta:

During early normal placental development, extravillous cytotrophoblasts of fetal origin invade the uterine spiral arteries of the decidua and myometrium. These invasive cytotrophoblasts replace the endothelial layer of the maternal spiral arteries, transforming them from small, high-resistance vessels into large-calibre capacitance vessels capable of providing adequate placental perfusion to nourish the fetus. In preeclampsia, this transformation is incomplete. Cytotrophoblast invasion of the spiral arteries is limited to the superficial decidua, and? the myometrial segments remain narrow.

In preeclampsia, cytotrophoblasts do not undergo this switching of cell-surface molecules and thus are unable to invade the myometrial spiral arterioles effectively. Angiogenic factors are thought to be important in the regulation of placental vascular development.Their receptors,Flt1[alsoknown as vascular endothelial growth factor receptor 1 (VEFGR-1)], VEGFR-2,Tie-1, and Tie-2, are essential for normal placental vascular development. Alterations in the regulation and signalling of angiogenic pathways in early gestation may also contribute to the inadequate cytotrophoblast invasion seen in preeclampsia.

Maternal Endothelial Dysfunction and Hemodynamic Changes

Preeclampsia appears to begin in the placenta; however, the target organ is the maternal endothelium. Generalized damage to the endothelium of the maternal kidneys, liver, and brain at the cellular level probably occurs following the release of vasopressive factors from the diseased placenta. Many serum markers of endothelial activation and endothelial dysfunction are deranged in women with preeclampsia; these markers include von Willebrand antigen, cellular fibronectin, soluble tissue factor, soluble E-selectin, platelet-derived growth factor, and endothelin.

Pathological Changes: Liver, Renal, and Cerebral Changes

Pathologic analysis of the organs of women suffering from preeclampsia and eclampsia show changes consistent with widespread hypoperfusion of organs. The liver and adrenals typically show infarction, necrosis, and intraparenchymal hemorrhage. The heart may reveal endocardial necrosis similar to that caused by hypoperfusion in hypovolemic shock. Injury to the maternal endothelium can be most clearly visualized in the kidney, which reveals the characteristic pathologic changes of preeclampsia. The term glomerular endotheliosis has been used to describe the ultrastructural changes in renal glomeruli, including generalized swelling and vacuolization of the endothelial cells and loss of the capillary space.


There are a number of mechanisms that contribute to the pathogenesis of preeclampsia. It is unclear whether the elucidated pathways are all interrelated, have synergistic effects, or act independently. However, endothelial damage induced by antiangiogenic factors, systemic inflammation, immunologic factors, and hypoxia all contribute to the development of this heterogeneous condition.

Altered Angiogenic Balance

Imbalance of innate angiogenic factors plays a key role in the pathogenesis of preeclampsia. Increased expression of sFlt1, associated with decreased PlGF and VEGF signalling, was the first abnormality described. Compared to normotensive controls, in patients with severe preeclampsia, free PlGF and VEGF levels are significantly decreased, and sFlt1 levels are significantly elevated.VEGF stabilizes endothelial cells in mature blood vessels and is particularly important in maintaining the endothelium in the kidney, liver, and brain.

sFlt1 antagonizes both VEGF and PlGF by binding the min the circulation and preventing interaction with their endogenous receptors. Placental expression of sFlt1 is increased in preeclampsia and is associated with a marked increase in maternal circulating sFlt1 .

VEGF is a central requirement for endothelial stability, and its blockade is an important part of the pathophysiology of preeclampsia. VEGF is necessary for glomerular capillary repair and may be particularly important in maintaining the health of the endothelium.

Women with preeclampsia also have alterations in placental hypoxia-inducible factor (HIF) and its targets. Women residing at high altitudes have similar alterations in HIF, and the rates of preeclampsia in populations at high altitudes are two-to fourfold greater. Many angiogenic proteins, including Flt-1, VEGFR-2, Tie-1, and Tie-2, are targets of HIF-1 regulation. These proteins are intimately linked to the regulation of normal placental vascular development. Invasive cytotrophoblasts express several other angiogenic factors regulated by HIF, including VEGF, PlGF, and VEGFR-1; expression of these proteins is altered in preeclampsia.TGF-β3, which has been shown to block cytotrophoblast invasion, is another HIF target. Hypoxia has been shown to upregulate expression and secretion of sFlt1 protein in primary trophoblast cultures from first-trimester placentas.

Renin-Aldosterone-Angiotensin Signaling

The renin-angiotensin-aldosterone axis is suppressed in preeclampsia. Normally, during pregnancy aldosterone and angiotensin are increased. Women with preeclampsia have increased vascular sensitivity to angiotensin II and other vasoconstrictive agents, and plasma renin/aldosterone are suppressed in preeclamptic patients relative to women with normal pregnancies. Angiotensin II is a peptide mediator that increases blood pressure by signalling arterial vasoconstriction after binding to its receptor.

Inflammation and Immunologic Alterations

The gravid uterus is a site of immune privilege that permits a fetal-placental unit, a semiallogeneic entity, to develop. Immune maladaptation is an important pathway that contributes to the inadequate invasion of cytotrophoblasts into the uterine decidua and may help explain why women with preeclampsia are typically nulliparous.


The presence of preeclampsia in a first-degree relative increases a woman’s risk of severe preeclampsia two-to fourfold even after controlling for body mass index, smoking status, and age.




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