Richard Hayman

Preeclampsia: the endothelium, circulating factor(s) and vascular endothelial growth factor.

It has been proosed that endothelial cell activation is the primary event in the multisystem disorder of preeclampsia. Evidence for endothelial involvement in this condition abounds. The best-characterized morphologic abnonnality of this syndrome, glomerular endotheliosis, involves endothelial cells. Also associated with preeclampsia is a loss of endothelial cell integrity, with the consequent increase in vascular penneability, and an increase in the circulating levels of the endothelial cell markers, fibronection, von Willebrand factor, tissue plasminogen activator, and plasminogen activator inhibitor-1. It is now well documented that endothelial activation contributes to the coagulation abnormalities observed in this disease. There is much evidence that the endothelial alteractions in preeclampsia results from one or more circulating factors. The incubation of cultured endothelial cells with serum or plasma samples, taken from normal pregnant women and women with preeclampsia, results in marked alterations in cell behavior and metabolic processes. More recently, experiments employing myographic techniques have demonstrated convincingly the effects of a circulating factor(s) on the function of endothelial cells of resistance arteries. Vascular endothelial growth factor (VEGF) possesses many of the characteristics required of a candidate circulating factor. It contains a hydrophobic secretory signal sequence, exerts in vitro effects specific to vascular endothelial cell, and promotes endothelial expression of procoagulant activity. Circulating VEGF concentrations are elevated in women with preeclampsia, and VEGF increases microvascular endothelial cell prostacyclin production in a dose-dependent manner, analogous to the acute effects of plasma from patients with preeclampsia. Similarly, in myographic studies, when myometrial resistance arteries are incubated with VEGF, there are dose-dependent alterations in endothelium-dependent behavior, mirrorng those found after incubation with plasma from patients with preeclampsia.

Plasma from women with pre-eclampsia induces an in vitro alteration in the endothelium-dependent behaviour of myometrial resistance arteries.

Objective To compare the in vitro effect of plasma from normal pregnant women and women with pre‐eclampsia on the endothelium‐dependent behaviour of myometrial resistance arteries from normal pregnant women.

Angiotensin-converting enzyme insertion-deletion polymorphism in normotensive and pre-eclamptic pregnancies

OBJECTIVE To investigate the hypothesis that pre-eclampsia is associated with a common insertion-deletion polymorphism in the angiotensin-converting enzyme gene. DESIGN Seventy-two women with pre-eclampsia and 83 normotensive pregnant women participated in the study. Pre-eclampsia was defined as a blood pressure exceeding 140/90 mm Hg in a previously normotensive woman, associated with proteinuria in excess of 300 mg/l in a 24 h collection. Samples for fetal genotyping were available from 66 pregnancies complicated by pre-eclampsia and 79 normotensive pregnancies. METHODS Maternal and fetal samples were genotyped at the insertion-deletion (I-D) polymorphism in intron 16 of the angiotensin-converting enzyme gene by the polymerase chain reaction followed by agarose electrophoresis. RESULTS Neither the I-D genotype distributions nor the allele frequencies differed significantly between pre-eclamptic and normotensive pregnancies in maternal or fetal samples (phi2 <0.3, not significant). The odds ratio for pre-eclampsia in women with the DD genotype, compared with the ID and II genotype, was 1.09 (95% confidence interval 0.55-2.16). The odds ratio associated with the DD genotype in the fetus was 1.14 (0.56-2.32). CONCLUSION This study has found no evidence that the insertion-deletion polymorphism in the angiotensin-converting enzyme gene is associated with pre-eclampsia.

Relationship of cell adhesion molecule expression to endothelium-dependent relaxation in normal pregnancy and pregnancies complicated with preeclampsia or fetal growth restriction.

Objectives: To determine the degree of endothelium-dependent relaxation in myometrial and omental resistance arteries from normal pregnancies and pregnancies complicated with preeclampsia or fetal growth restriction (FGR) (compromised pregnancy group), and to correlate the results with the endothelial surface expression of cell adhesion molecules (CAMs) in the same vessels. Methods: Parallel wire myograph was used to assess the relaxation of omentum or myomentrial vessels obtained from monpregnant women (n = 3), women with normal pregnancies (n = 11), and women with pregnancies complicated by preeclampsia or fetal growth restriction (n = 10). These resistance vessels were constricted with incremental concentrations of vasopressin (10-10 mol/L to 3.3 × 10-8 mol/L) prior to the addition of incremental concentrations of bradykinin (10-10 mol/L to 3.3 × 10-6 mol/L). Immunohistochemistry was used to assess the endothelial expression of the CAMs E-selectin, ICAM-1, VCAM-1, and PECAM. Results: A significant reduction in endothelium-dependent relaxation of myometrial vessels was found in the compromised pregnancy group when compared with both the normotensive pregnant group and the nonpregnant group. This reduction was not noted with omenal vessels. All vessels in the nonpregnant group, normal pregnant group, and compromised pregnancy group expressed PECAM and ICAM-1 on the endothelium. There was no difference in intensity of immunostaining between the groups. None of the vessels in any of the groups expressed VCAM-1 or E-selectin. Conclusions: We found no evidence that impaired relaxation responses to bradykinin are linked to altered expression of CAMs in preeclampsia and FGR. These results suggest that increased CAM expression occurs in a vascular bed separate from those investigated in the present study. Possible sites for his would be in the microcirculation of organs such as the kidney.

Relationship between myometrial resistance artery behavior and circulating lipid composition

OBJECTIVES The study investigated whether an inducible alteration in endothelium-dependent relaxation in myometrial vessels could be correlated with plasma lipid composition. STUDY DESIGN Myometrial resistance vessels were obtained from 10 women with normal pregnancy undergoing elective cesarean delivery. Paired vessels were incubated with plasma samples from patients with preeclampsia or from women with normal pregnancy and mounted on a wire myograph. After contraction with vasopressin, the degree of relaxation in response to bradykinin was observed. Plasma samples were assayed for cholesterol, triglycerides, apolipoprotein A1, and apolipoprotein B. RESULTS A significant reduction in endothelium-dependent relaxation with respect to control values was observed in vessels incubated in plasma samples from patients with preeclampsia (P =.0001). Although no significant difference was noted between the lipid profiles of the 2 subgroups, a significant correlation was found between the vessel relaxation and the plasma content of apolipoprotein A1 (R2 = 0.36, P = .025). CONCLUSION Plasma samples from women with pregnancies complicated by preeclampsia are capable of altering endothelium-dependent myometrial vessel relaxation. A significant relationship between the apolipoprotein A1 concentration and endothelial behavior supports the suggestion that aberrant lipid metabolism may be involved in the endothelial dysfunction characteristic of preeclampsia.