Author: Zhang Chen, Qi Hongbo
Unit: Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University
Preeclampsia is a syndrome characterized by high blood pressure combined with proteinuria or end-organ dysfunction after 20 weeks of pregnancy. Its diagnostic criteria are:
The pathogenesis of preeclampsia may involve both maternal and fetal/placental factors. However, the triggering factors of abnormal placental development and subsequent cascade events are still unclear. This article will sort out the possible pathogenesis of preeclampsia.
The placenta plays a key role in the pathophysiology of preeclampsia: placental tissue is a necessary factor for preeclampsia, but the fetus is not; preeclampsia can be cured within days to weeks after the placenta is delivered.
1. Abnormal remodeling of spiral arteries
In a normal pregnancy, a part of the placental trophoblast cells infiltrates the endothelium of the maternal spiral artery through the decidua. The maternal spiral artery is the terminal branch of the uterine artery that supplies blood to the developing fetus/placenta; the other part is infiltrated through the myometrium. The media with muscular structure changes the blood vessels from small muscular arteries to large-volume blood vessels with low resistance, increasing blood flow to the placenta.
In preeclampsia, the cytotrophoblast cells can infiltrate the decidua of the spiral artery, but cannot pass through the myometrium. Because the muscular elastic blood vessel wall cannot be replaced by cellulose-like substances, the spiral artery cannot be transformed into a large tortuous vascular channel, but is still narrow, resulting in insufficient placental perfusion. This leads to a variety of adverse pregnancy outcomes, but the mechanism is still unclear.
2.Defects in trophoblast cell differentiation
Trophoblast cell differentiation defect is a possible mechanism leading to abnormal infiltration of spiral artery trophoblast cells. In the normal differentiation process, the invading trophoblast cells can change the expression of their own adhesion molecules, from epithelial cell characteristics to endothelial cell characteristics. This process is called pseudoangiogenesis. The trophoblast cells obtained from women with preeclampsia did not show up-regulation of adhesion molecule expression or pseudo-angiogenesis.
3.Hypoperfusion, hypoxia, ischemia
Exposure to paternal/fetal antigens can resist preeclampsia: women with less paternal antigen exposure have a higher risk of preeclampsia.
In women with preeclampsia, there are immunological abnormalities similar to those seen in organ rejection graft-versus-host disease.
The placental bed biopsy of women with preeclampsia revealed an increase in the infiltration of dendritic cells in the decidua tissue of preeclampsia. This may lead to changes in the presentation of maternal and fetal antigens at the decidual level, which in turn leads to abnormal implantation or changes in the maternal immune response to fetal antigens.
三、Increased sensitivity to angiotensin II
It has been reported that patients with preeclampsia have increased sensitivity to angiotensin II, which may be related to the up-regulation of bradykinin (B2) receptors in these patients. Up-regulation of B2 receptors can lead to heterodimerization of B2 receptors with angiotensin II type I receptor (AT1); in in vitro experiments, the AT1/B2 heterodimer can increase the resistance to angiotensin II ’S response.
Other animal experiments have shown that the endothelial dysfunction induced by anti-angiogenic factors in the circulation is sufficient to increase the body's sensitivity to angiotensin II. These studies provide a strong biological basis for the treatment of preeclampsia and can help to study compounds that improve endothelial health.
Although most cases of preeclampsia are sporadic, genetic factors are also believed to play a role in disease susceptibility:
1. Calcium intake
Some epidemiological studies have found that for high-risk women, low calcium intake is associated with an increased incidence of preeclampsia, and calcium supplementation is associated with the prevention of preeclampsia; these results suggest that low dietary calcium intake may be eclampsia Early risk factors, but the relevant mechanism is still unclear.
2. Body mass index
A prospective study confirmed that there is a linear relationship between increased BMI and increased risk of preeclampsia. Obesity may increase the susceptibility to preeclampsia, because obesity-induced chronic inflammation and endothelial dysfunction may have a synergistic effect with placental angiogenesis factors, leading to microvascular disease in preeclampsia.
六、Systemic endothelial dysfunction
Increased placental expression and secretion of sFlt-1 play a key role in the pathogenesis of preeclampsia. However, it is currently unclear what triggers the increase in sFlt-1 production in the placenta:
（1）Administration of sFlt-1 in pregnant rats can cause albuminuria, hypertension and unique renal pathological changes of glomerular endothelial hyperplasia;
（2）Removal of sFlt-1 from the tissue culture supernatant of preeclampsia can restore endothelial function and restore angiogenesis to normal levels. On the contrary, exogenous administration of VEGF and PlGF can reverse the anti-angiogenic state caused by excessive sFlt-1;
（3）Compared with controls with normal blood pressure, in women with preeclampsia, the level of circulating sFlt-1 increased, and the levels of free VEGF and free PlGF decreased;
（4）The changes of sFlt1 and PlGF concentrations are related to the maternal and neonatal outcomes related to preeclampsia.
2.Soluble endothelial factor
The soluble form of placental-derived endothelial factor is called soluble endothelial factor (soluble endothelial factor, sEng), which is an anti-angiogenic protein and another important mediator of preeclampsia:
（1）2-3 months before the appearance of clinical signs of preeclampsia, sEng in the serum of women with preeclampsia increases, and is related to the severity of the disease; sEng levels decrease after delivery. The increase in the level of sEng and the increase in the ratio of sFlt-1 to PlGF have the most predictive significance for the occurrence of preeclampsia.
（2）sEng can inhibit the signal transmission of TGF-β-1 in endothelial cells and prevent eNOS activation and vasodilation mediated by it, indicating that the dysregulation of TGF-β-1 signal transmission may be involved in the pathogenesis of preeclampsia.
There may be signs of maternal inflammation during normal term pregnancy, which can be exacerbated in the case of preeclampsia. There is a hypothesis that the fragments of syncytiotrophoblasts in the circulation can cause maternal inflammation and cause certain maternal diseases. Placental hypoxia aggravates placental necrosis and apoptosis, resulting in freeingDNA is released into the maternal circulation and plays a role in driving the systemic inflammatory response in preeclampsia.