Early Onset Preeclampsia Is Associated With Glycocalyx Degradation and Reduced Microvascular Perfusion

Tracey L Weissgerber, Oscar Garcia-Valencia, Natasa M Milic, Elizabeth Codsi, Hajrunisa Cubro, Meryl C Nath, Wendy M White, Karl A Nath, Vesna D Garovic, Tracey L Weissgerber, Oscar Garcia-Valencia, Natasa M Milic, Elizabeth Codsi, Hajrunisa Cubro, Meryl C Nath, Wendy M White, Karl A Nath, Vesna D Garovic

Abstract

Background The endothelial glycocalyx is a vasoprotective barrier between the blood and endothelium. We hypothesized that glycocalyx degradation is present in preeclampsia, a pregnancy-specific hypertensive disorder characterized by endothelial dysfunction and activation. Methods and Results We examined the sublingual glycocalyx noninvasively using sidestream dark field imaging in the third trimester among women with normotensive pregnancies (n=73), early (n=14) or late (n=29) onset preeclampsia, or gestational diabetes mellitus (n=21). We calculated the width of the glycocalyx that was permeable to red blood cells (called the perfused boundary region, a measure of glycocalyx degradation) and the percentage of vessels that were filled with red blood cells ≥50% of the time (a measure of microvascular perfusion). In addition, we measured circulating levels of glycocalyx components, including heparan sulfate proteoglycans, hyaluronic acid, and SDC1 (syndecan 1), in a subset of participants by ELISA . Repeated-measures ANOVA was performed to adjust for vessel diameter and caffeine intake. Women with early onset preeclampsia showed higher glycocalyx degradation, indicated by a larger perfused boundary region (mean: 2.14 [95% CI, 2.05-2.20]), than the remaining groups (mean: normotensive: 1.99 [95% CI, 1.95-2.02], P=0.002; late-onset preeclampsia: 2.01 [95% CI, 1.96-2.07], P=0.024; gestational diabetes mellitus: 1.97 [95% CI, 1.91-2.04], P=0.004). The percentage of vessels that were filled with red blood cells was significantly lower in early onset preeclampsia. These structural glycocalyx changes were accompanied by elevated plasma concentrations of the glycocalyx components, heparan sulfate proteoglycans and hyaluronic acid, in early onset preeclampsia compared with normotensive pregnancy. Conclusions Glycocalyx degradation and reduced microvascular perfusion are associated with endothelial dysfunction and activation and vascular injury in early onset preeclampsia.

Keywords: gestational diabetes mellitus; microcirculation; preeclampsia/pregnancy; vascular glycocalyx.

Figures

Figure 1
Figure 1
Glycocalyx measurements. A, The noninvasive camera records live video of RBCs moving through sublingual vessels. B, Schematic illustration of glycocalyx structure. C, The healthy glycocalyx is relatively impermeable to RBCs, resulting in a small PBR. D, Glycocalyx damage allows RBCs to penetrate further into the glycocalyx, increasing PBR width. PBR indicates perfused boundary region; RBC, red blood cell.
Figure 2
Figure 2
Vessel segments in each size category among pregnant women. Pooled data from 73 normotensive pregnant women, 21 women with gestational diabetes mellitus, 29 women with late‐onset preeclampsia, and 14 women with early onset preeclampsia. Values for the number (A) and percentage (B) of segments in each size category are the average of 3 trials.
Figure 3
Figure 3
Effect of caffeine intake on noninvasive glycocalyx measurements in normotensive pregnant women. PBR (A) and the percentage of vessel segments that were filled with RBCs (B) were compared from 23 women who had caffeine in the 6 hours before the test and 50 women who did not have caffeine. Data were analyzed by repeated‐measures ANOVA with caffeine intake (yes vs no) as a between‐subjects factor and vessel size as a within‐subjects factor. Vessel size included 12 categories (5–16 μm), based on the median width of the RBC column. The main effect of caffeine intake was not statistically significant for PBR (mean: caffeine: 1.946 [95% CI, 1.888–2.005]; no caffeine: 2.003 [95% CI, 1.963–2.043]; F=2.501, df=1, P=0.118). There was a significant main effect of caffeine on the percentage of segments filled with RBCs (mean: caffeine: 0.579 [95% CI, 0.560–0.599]; no caffeine: 0.548 [95% CI, 0.535–0.562]; F=6.806, df=1, P=0.011). Post hoc analyses were performed with a least significant differences test. PBR indicates perfused boundary region; RBC, red blood cell.
Figure 4
Figure 4
Relationship between pregnancy outcome and noninvasive glycocalyx measurements. PBR (A) and the percentage of vessel segments that were filled with RBCs (B) for vessel sizes 5 to 16 μm, among women with different pregnancy outcomes after adjusting for caffeine intake. See statistical results in Table S5. GDM indicates gestational diabetes mellitus; PBR indicates perfused boundary region; PE, preeclampsia; RBC, red blood cell.
Figure 5
Figure 5
Plasma SDC1 (syndecan 1) concentrations in women with normotensive pregnancies, early and late‐onset preeclampsia, and GDM. SDC1 was correlated with gestational age (ρ=0.454, P=0.002, Spearman correlation coefficient; 1 outlier was excluded from this analysis). GDM indicates gestational diabetes mellitus.

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