High-density lipoprotein (HDL) is a circulating complex of lipids and proteins known primarily for its role in reverse cholesterol transport and consequent protection from atheroma. In spite of this, therapies aimed at increasing HDL concentration do not reduce the risk of cardiovascular disease (CVD), and as such focus has shifted towards other HDL functions protective of vascular health – including vasodilatory, anti-inflammatory, antioxidant and anti-thrombotic actions. It has been demonstrated that in disease states such as CVD and conditions of insulin resistance such as Type 2 diabetes mellitus (T2DM), HDL function is impaired owing to changes in the abundance and function of HDL-associated lipids and proteins, resulting in reduced vascular protection. However, the gold standard density ultracentrifugation technique used in the isolation of HDL also co-isolates extracellular vesicles (EVs). EVs are ubiquitous cell-derived particles with lipid bilayers that carry a number of lipids, proteins and DNA/RNA/miRNAs involved in cell-to-cell communication. EVs transfer their bioactive load through interaction with cell surface receptors, membrane fusion and endocytic pathways, and have been implicated in both cardiovascular and metabolic diseases – both as protective and pathogenic mediators. Given that studies using density ultracentrifugation to isolate HDL also co-isolate EVs, biological effects attributed to HDL may be confounded by EVs. We hypothesise that some of HDL’s vascular protective functions in cardiovascular and metabolic disease may be mediated by EVs. Elucidating the contribution of EVs to HDL functions will provide better understanding of vascular protection and function in conditions of insulin resistance and potentially provide novel therapeutic targets for such diseases.

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Objective: High-density lipoprotein (HDL) has well-established anti-atherosclerotic properties in the non-pregnant population. HDL may have a potential role in protecting maternal vascular function during pregnancy that fails to occur in preeclampsia. HDL function is determined by its protein and lipid composition. This study aimed to examine protein composition of HDL at different gestations throughout healthy pregnancy and to compare HDL proteome in the third trimester of healthy pregnancy and preeclampsia. Design and method: HDL was isolated from two cohorts of n = 10 healthy pregnant women at 8 different timepoints throughout pregnancy; pre-pregnancy, week 4.6, week 6.1, week 8.4, (cohort 1) and week 15, week 25, week 35 and 3 months post-natal (cohort 2), and from healthy pregnant (n = 10) and preeclampsia (n = 6) women at the third trimester. The proteome of HDL was measured by nano liquid chromatography coupled to tandem mass spectrometry (nLC-MS/MS). Results: There were 16 proteins in HDL that showed significant differences throughout healthy pregnancy which were apolipoprotein A-IV, apolipoprotein C-II, apolipoprotein C-III, apolipoprotein C-IV, apolipoprotein F, apolipoprotein L-I, angiotensinogen, alpha-1-acid glycoprotein 2, alpha-1-antitrypsin, cathelicidin antimicrobial peptide, fibrinogen alpha chain, fibrinogen beta chain, prenylcysteine oxidase 1, serum amyloid a-I, serum paraoxonase/lactonase 3 and vitronectin. In preeclampsia, HDL apolipoprotein A-I was lower than healthy pregnancy, while HDL alpha-1-antitrypsin, pigment epithelium-derived factor and vitamin D-binding protein were higher. Conclusions: There were significant differences in the protein composition of HDL during pregnancy and between healthy pregnancy and preeclampsia in the third trimester. These compositional differences may be involved in HDL function and may indicate HDL's role in vascular protection in pregnancy.