The glycocalyx is a negatively charged, complex meshwork of glycoproteins, glycolipids produced by cells, along with associated proteins bound primarily to heparin sulfate side-chains of proteoglycans. Endothelial and epithelial cells produce distinct apical cell surface glycocalyx, which have significant functional roles for both cell type. The endothelial glycocalyx acts as a mechano-shear transducer for nitric oxide release, attenuates inflammatory cell and platelet adhesion, and regulates vascular osmotic pressure gradients, and lipid transport. The pregnancy disorder preeclampsia (PE) has been shown to encompass dysfunction within these inter-related systems that can be influenced by gycocalyx integrity. We propose that glycocalyx disruption and shedding, within the syncytiotrophoblasts (epithelial cells of the placental villi), and maternal vascular endothelium is present and contributory to in a final common pathway to preeclampsia. In the current proposal we hypothesize that disruption and loss glycocalyx components accompanies preeclampsia. We will utilize newly developed noninvasive technologies of side-stream darkfield (SDF) imaging couple with Glycocheck software to quantify glycocalyx dimensions in the sublingual microcirculation of pregnant women and post-partum (Aim 1). We will determine if this imaging measure of glycocalyx is representative of ex vivo assessments of glycocalyx in the maternal vasculature (subcutaneous fat), placental syncytiotrophoblasts, vessels in the placental villi and umbilical vein (Aim 2) and if components of shed glycocalyx in the circulation or urine of pregnant women change with preeclampsia (Aim 2). Lastly, we will determine if reduced glycocalyx depth or other measures of shed or disrupted glycocalyx correlate with increased severity of preeclampsia or specific criteria of severity (Aim 3). If disruption of the maternal endothelial glycocalyx is demonstrated both in vivo using non-invasive side-stream darkfield imaging and ex vivo and a relationship to severity of PE is established, in subsequent studies we would plan to examine: the longitudinal progression of glycocalyx disruption, the implications of glycocalyx disruption to placental and vascular function, and potential therapeutic strategies targeting the glycocalyx. The ultimate goal of this research is to develop therapeutic strategies to prevent PE.
Despite major increases in our understanding of the pathophysiology of preeclampsia (PE) in the last 20-30 years, and our recognition of life-long risks of PE to both mother and baby, therapeutic strategies to prevent PE are still lacking. We propose that PE is a heterogenous disorder of pregnancy, arising due to maternal and pregnancy specific factors that converge on functional and structural breakdown of the maternal endothelial glycocalyx, resulting in the pathognomonic manifestations of PE. If successful this project would establish the glycocalyx as a novel potential therapeutic target for the prevention of PE.
|Gandley, Robin E; Althouse, Andrew; Jeyabalan, Arundhathi et al. (2016) Low Soluble Syndecan-1 Precedes Preeclampsia. PLoS One 11:e0157608|