Rose Webster

Vascular biology of preeclampsia

Summary.  Preeclampsia, a pregnancy‐specific syndrome characterized by hypertension, proteinuria and edema, resolves on delivery of the placenta. Normal pregnancy is itself characterized by systemic inflammation, oxidative stress and alterations in levels of angiogenic factors and vascular reactivity. This is exacerbated in preeclampsia with an associated breakdown of compensatory mechanisms, eventually leading to placental and vascular dysfunction. The underlying pathology of preeclampsia is thought to be a relatively hypoxic or ischemic placenta. Both the placenta and maternal vasculatures are major sources of reactive oxygen and nitrogen species which can interact to produce peroxynitrite a powerful prooxidant that covalently modifies proteins by nitration of tyrosine residues, to possibly alter vascular function in preeclampsia. The linkage between placental hypoxia and maternal vascular dysfunction has been proposed to be via placental syncytiotrophoblast basement membranes shed by the placenta or via angiogenic factors which include soluble flt1 and endoglin secreted by the placenta that bind vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) in the maternal circulation. There is also abundant evidence of altered reactivity of the maternal and placental vasculature and of the altered production of autocoids in preeclampsia. The occurrence of preeclampsia is increased in women with preexisting vascular disease and confers a long‐term risk for development of cardiovascular disease. The vascular stress test of pregnancy thus identifies those women with a previously unrecognized at risk vascular system and promotes the development of preeclampsia. Preexisting maternal vascular dysfunction intensified by placental factors is possibly responsible for the individual pathologies of preeclampsia.

Differences in the proteome profile in placenta from normal term and preeclamptic preterm pregnancies

The aim of this study was to use proteomic approaches to examine differences in protein expression in placentae from normal term and preterm preeclamptic pregnancies and to validate the data thus obtained by other independent methods. Using 2‐DE we found that 80% of the proteins were present in both normal and preeclamptic placentae. However, 26 proteins in the normal term placentae were not matched in the preterm preeclamptic group. Six proteins showed increased intensity and one protein was down‐regulated in preeclampsia. Four of the seven proteins that were altered in preeclampsia were further analyzed by Western blot and immunohistochemistry. Identification by MS techniques revealed these proteins to be involved in regulatory pathways activated by stress. This is significant because preeclampsia is a multisystem disorder in human pregnancies that results in considerable oxidative and nitrative stress. Three proteins identified by MS to be Hsp27, catalase, and glucose‐regulated protein were confirmed by Western blot analysis to be significantly up‐regulated in preeclampsia. Endothelial monocyte‐activating polypeptide was shown to be down‐regulated in preeclampsia by 2‐DE and MS.

Elucidation of the molecular mechanisms of preeclampsia using proteomic technologies

Preeclampsia, a disease of pregnancy, is a multisystem disorder associated with elevated maternal blood pressure, proteinurea, oedema, and fetal abnormalities. It is a major cause of mortality, morbidity, perinatal death, and premature delivery. Despite active research in the past decade, there is yet no definitive cure for preeclampsia. The disease has been treated symptomatically with antihypertensives, antieclamptics, bed rest, and a whole gamut of isolated therapies. In an attempt to understand the molecular basis of this disease and many other fatal diseases including cancer and heart disease, the scientific community has been turning to understanding the genome and more lately the “proteome”. Proteomics enables researchers to identify all proteins expressed in a cell or organ and detect any PTM in the protein expression patterns. Deciphering the placental proteome and studying the differences in protein expression patterns in the normal as against the preeclamptic proteome might possibly in future lead to early detection and therapeutic targeting of preeclampsia.