In humans, the risk factors of essential hypertension and pre-eclampsia overlap considerably and, indeed, pre-existing hypertension increases the risk of pre-eclampsia (Eskenazi et al., 1991; Sibai et al., 1995). It is therefore not surprising that some genes that have been implicated as risk factors for pre-eclampsia, AGT (encoding angiotensinogen, a precursor of the vasoconstrictor angiotensin) (Ward et al., 1993) and NOS3 (encoding endothelial nitric oxide synthetase, eNOS) (Arngrimsson et al., 1997), are also risk factors for essential hypertension. Notably, the associations with the AGT and NOS3 genes have not been confirmed in all affected families (Lachmeijer et al., 2002; Roberts and Cooper, 2001), implying that AGT and NOS3 mutations likely do not explain all cases of pre-eclampsia. Based on these human studies alone it is difficult to say whether hypertension alone is sufficient to promote the development of pre-eclampsia. However, recent work in mice suggests that it is.
Table 14.2. Rodent models of pre-eclampsia and intrauterine growth restriction
High BP Proteinuria Renal lesions Placental changes IUGR
BPH/5 strain REN-AGT transgenic p57Kip2 mutant
Endotoxin-induced Soluble Flt1
administration Esxl mutant
Gestational hypertension Yes Placental development Yes
Inflammatory disease Endothelial dysfunction
Yes Yes Yes
Yes Yes Yes
Labyrinth, giant cells
Vascularization of Yes labyrinth Reduced nutrient Yes transport Constricted spiral ? arteries
The BPH/5 strain of mice was identified as a borderline hypertensive line that in follow up studies was found to develop high blood pressure during pregnancy. Whereas the mean arterial blood pressure in normal mice falls during mid to late gestation, it increases in BPH/5 pregnant females (Davisson et al., 2002). This implies that a pregnancy-specific factor interacts with and exacerbates the propensity for increased blood pressure. Interestingly, the BPH/5 mice also develop renal glomerulosclerosis and proteinuria in late pregnancy. While the gene underlying the defect is unknown, the data are consistent with the hypothesis that hypertension, at least during pregnancy (even an otherwise normal pregnancy), is sufficient to initiate the full spectrum of clinical signs of pre-eclampsia. Notably, proteinuria and glomerulosclerosis are also observed when the renin—angiotensin system (RAS) is constitutively activated in transgenic mice even in the non-pregnant state (Caron et al., 2002). Overexpression of angiotensinogen alone is not sufficient to produce pre-eclampsia, even though blood pressure is higher than in wildtype mice due to a failure to decline during pregnancy (Hefler et al., 2001), indicating that placental renin is required to cause the full spectrum of disease.
The normal drop in blood pressure during healthy pregnancy in humans and rodents implies that the feto-placental unit regulates maternal blood pressure. The placenta is a major source of vasoactive compounds such as nitric oxide, adrenomedullin, prostaglandins and prostacyclins (Cross, 1996; Cross et al., 2002), as well as renin (Cooper et al., 1999; Xia et al., 2002), an enzyme that cleaves angiotensinogen to produce the vasoconstrictor angiotensin II. Therefore, through these and potentially other factors, the placenta is likely to be a direct regulator of maternal cardiovascular function though formal proof for most factors is largely missing. Female mice that are deficient for NOS3 (eNOS) show higher blood pressure throughout pregnancy even if they are carrying non-mutant conceptuses (Hefler et al., 2001), but no attempt has yet been made to assess the relative roles of feto-placental production. Adrenomedullin appears to have an essential role in blood pressure regulation (Shindo et al., 2001), although homo-zygous mutant embryos die in utero precluding a thorough analysis of placentally derived adreno-medullin in regulating maternal cardiovascular function. The role of placental renin has been demonstrated in a transgenic mouse model in which females carrying an angiotensinogen (AGT) transgene are mated to males that are transgenic for a renin (REN) gene. The females develop gestational hypertension as a result of placental expression of renin and also proteinuria and glomerulosclerosis (Takimoto et al., 1996), implying that hypertension can initiate pre-eclampsia as in the BPH/5 mouse model.
Mice that are deficient for the cyclin-dependent kinase inhibitor, p57Kip2, are the basis of an interesting model of pre-eclampsia because placental lesions are observed and because the maternal disease is secondary to the placental defects (Kanayama et al., 2002; Takahashi et al., 2000). In this model, females that carry p57Kip2-deficient pups develop pre-eclampsia, even though they have normal p57Kip2 function and, as such, the maternal disease is due to the mutation impacting feto-placental development. The mutant pups are often growth-restricted and show a significantly reduced villous surface area in the placenta (Takahashi et al., 2000), and these changes are sufficient to account for the fact that mutant embryos either die in utero or, even if they survive to term, are growth-restricted. An important feature of this model is that pre-eclampsia develops even if not all of the conceptuses in a litter are mutant. It is unclear if the onset of the disease is correlated with the absolute number of mutant conceptuses or with the relative proportion of mutant and wildtype ones. It would be fruitful to explore this issue in order to distinguish between two main hypotheses that concern how abnormal placental function may contribute to the disease: that the maternal disease is initiated by failure of specific placental functions related to vascular adaptation to pregnancy, or that feto-placental undernutrition/hypoxia leads to production of ''toxic'' compounds.
Intrauterine growth restriction due to placental defects
There are several mouse models in which placental function is compromised in different ways resulting in fetal growth restriction or even death (Table 14.2). Esx1 mutants show a defect in the vascularization of the labyrinth layer of the placenta (Li and Behringer, 1998). Mice in which placental expression of Igf2 is reduced by gene knockout (Constancia et al., 2002) or in transgenics overexpressing an IGF binding protein have reduced placental transport function (Crossey et al., 2002). Rag2/gc mutant mice lack natural killer cells and show a relative constriction of the spiral arteries presumably leading to ''pre-placental'' undernutrition of the fetuses (Croy et al., 2000). None of these models have been examined in detail to determine if the females develop pre-eclampsia, though it would be interesting to do so in order to compare the outcomes of these mice with the p57Klp2 mutants.
There is now considerable evidence of systemic endothelial activation during pre-eclampsia, at least during the end stages of disease (Roberts and Lain, 2002). In rats, systemic administration of low-dose endotoxin (Faas et al., 1995; Sakawi et al., 2000; Wardle, 1976) or soluble-Fltl (an antagonist of vascular endothelial growth factor, VEGF) (Maynard et al., 2003) results in endothelial dysfunction and development of hypertension, proteinuria and glomerulosclerosis. Interestingly, the dose of endotoxin that is required to induce these pathologies in pregnancy animals is considerably lower than in non-pregnant females (Faas et al., 1995). This suggests that the systemic endothelium may be more sensitive during pregnancy. Alternatively, the difference in sensitivity may be that the primary target of the endotoxin may be the feto-placental unit and not the maternal system per se. The latter possibility should be explored by careful histological examination of the placenta.
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Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...