Paradoxes: Cholesterol and Hypoxia in Preeclampsia

Abstract

Preeclampsia, a hypertensive disease of pregnancy of unknown etiology, is intensely studied as a model of cardiovascular disease (CVD) not only due to multiple shared pathologic elements but also because changes that develop over decades in CVD appear and resolve within days in preeclampsia. Those affected by preeclampsia and their offspring experience increased lifetime risks of CVD. At the systemic level, preeclampsia is characterized by increased cellular, membrane, and blood levels of cholesterol; however, cholesterol-dependent signaling, such as canonical Wnt/βcatenin, Hedgehog, and endothelial nitric oxide synthase, is downregulated indicating a cholesterol deficit with the upregulation of cholesterol synthesis and efflux. Hypoxia-related signaling in preeclampsia also appears to be paradoxical with increased Hypoxia-Inducible Factors in the placenta but measurably increased oxygen in maternal blood in placental villous spaces. This review addresses the molecular mechanisms by which excessive systemic cholesterol and deficient cholesterol-dependent signaling may arise from the effects of dietary lipid variance and environmental membrane modifiers causing the cellular hypoxia that characterizes preeclampsia.

Keywords: Hedgehog (Hh); Wnt/βcatenin; cholesterol; dietary lipids; dyslipidemia; endothelial nitric oxide synthase; hypoxia inducible factors; membrane biophysics; oxidative stress; preeclampsia.

Figure 1

Representative membrane lipids. Note the very low melting points of the highly unsaturated omega-6 and omega-3 essential fatty acids, as well as the very-short-chain saturated butyric acid (red, bright orange, and yellow). Monounsaturated fatty acids, such as oleic acid, which is abundant in olive oil or medium-chain saturated fatty acids, such as lauric acid found in coconut oil, have moderate melting points (green). Long-chain saturated fatty acids (LCSFAs) with no double bonds, such as palmitic and stearic acids found in beef, have high melting points and high cholesterol affinity (purple, blue, and greys). Although cholesterol (white) has a very high melting point, due to its planar head and short tail, it acts as a plasticizer to maintain normal viscosity over a wide range of membrane compositions. Cholesterol also reduces membrane permeability to water. Phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS) are pictured as representative glycerophospholipids (top left). Each phospholipid head group has two fatty acids attached, with the most usual arrangement being a saturated fatty acid at position one and an unsaturated fatty acid at position two [86]. (Parts of figure used with permission from Hart NR. A theoretical model of dietary lipid variance as the origin of primary ciliary dysfunction in preeclampsia [87]).

Figure 2

In vitro spontaneous lipid bilayer formation. (A) Upon mixing phospholipids with similar melting points and cholesterol in an aqueous medium, a homogeneous bilayer forms. (B) When a low-melting-point lipid is added to the mixture the lipids do not mix homogeneously allowing areas with greater and lesser order to form. PUFA’s aversion to cholesterol is the driving force in this process of phase separation in which areas of high-melting-point lipids gather with cholesterol away from low-melting-point PUFAs. The thicker, denser blue area in the middle of the bilayer membrane represents a liquid-ordered area, which corresponds to rafts in living cells. CVD is characterized by excess membrane rafts.

Figure 3

Dietary lipids and membrane viscosity. When the membrane homeostasis of laboratory animals is challenged with a high level of dietary low-melting-point PUFAs, fatty acids are rapidly incorporated into membranes, causing the bilayer to become excessively fluid (wavey orange line). To compensate, the increased synthesis and incorporation of cholesterol and high-melting-point LCSFAs increases the membrane rigidity (straight purple line), allowing membranes to regain normal viscosity (green moderately wavey line).

Figure 4

Excessively fluid bilayers cause compensatory increases in the cytoskeleton.

Figure 5

Oxygen diffusion in healthy membranes. Healthy membranes present almost no barrier to oxygen diffusion. With primarily moderate-melting-point lipids, moderate cytoskeletal elements, less than 1% PUFAs, small rafts, and minimal molecules with very high cholesterol affinity, such as LCSFAs and trans unsaturated fatty acids, the total cholesterol content of a healthy membrane is moderate. The cholesterol present is associated with molecules with low or moderate cholesterol affinity, making it accessible and available for signaling.

Figure 6

Oxygen diffusion in preeclampsia membranes. In preeclampsia, membranes have more rafts with increased cholesterol and LCSFAs, which increase membrane thickness and reduce trans-membrane oxygen diffusion. Areas with increased PUFAs may have increased cytoskeletal elements and increased stiffness. These factors reduce trans-membrane oxygen diffusion. Cholesterol/cholesterol bilayer areas reduce oxygen D_M to 10% that of a health membrane.

Figure 7

Oxygen’s transplacental path to fetal tissue Moving from a maternal RBC to fetal tissue, an oxygen molecule must pass through 10 membranes: 1. maternal RBC, 2. villous trophoblast maternal lumen side, 3. villous trophoblast stromal side, 4. fetal endothelial cell stromal side, 5. fetal endothelial cell lumen side, 6. fetal RBC at placental villus, 7. fetal RBC at fetal endothelial cell, 8. lumen side fetal endothelial cell, 9. tissue side fetal endothelial cell, 10. fetal tissue cell. Increased impedance at each membrane may become clinically relevant in creating the measured increased oxygenation of maternal villous blood and decreased fetal oxygenation.