The overall direction of my research is to investigate a role for human cytomegalovirus (HCMV) in cardiovascular disease such as pre-eclampsia through its modulation of a bioactive lipid, sphingosine 1-phosphate (S1P).
I am examining the effects of HCMV on four characteristics of pre-eclampsia: (1) the importance of the placenta; (2) the increased systemic vascular constriction and hypertension and (3) abnormal uterine artery perfusion and (4) elevated inflammatory responses. Each of these areas of research is briefly outlined below.
The placenta is thought to release a factor(s) into the maternal circulation that subsequently results in the endothelial dysfunction and vascular constriction so characteristic of pre-eclampsia. My hypothesis is that reactivation or reinfection of HCMV in pregnancy results in preferential accumulation and protection of virus in the placenta.The placenta then acts as a viral reservoir by continuously releasing virus into the maternal circulation. One of my research goals is to examine the role of the placenta as a viral reservoir.
An important function of S1P is the regulation of vascular tone. I am investigating the mechanism by which HCMV affects the vasculature by evaluating viral effects on enzymes involved in the metabolism of S1P. We have found that HCMV increases the production and activity of two key enzymes in the endothelium that likely result in increased S1P levels. This could lead to increased vasoconstriction and hypertension. We are now extending these results in cell culture to in vivo animal studies and vascular function studies using isolated human arteries.
Since uteroplacental perfusion is important to pregnancy outcome and reduced perfusion has been described in pre-eclampsia, another area of research includes examining the uterine artery response to S1P at various stages of pregnancy and determining whether that response is impaired in a mouse model of CMV infection. We are investigating the mechanism by which this occurs using various pharmacological inhibitors.
S1P is also an important mediator of angiogenesis, cell migration and lymphocyte recirculation. A series of studies in the Hemmings laboratory, therefore, focuses on the role of S1P in normal pregnancy including placental development and immunological adaptations essential to a successful pregnancy such as alterations in TH1 and TH2 type immune responses.