Polarized Secretion of Endothelial Cells in Early Atherosclerosis

Abstract

The endothelium is a monolayer of endothelial cells that lines the innermost layer of the
blood vessels and makes direct contact with both the circulating blood and the vascular tissues.
It is one of the largest endocrine organs in the body, which secrete various regulatory
factors to maintain vascular health. The secretion of endothelial-derived substances is polarized
and under strict regulation. A recent study from my group has mapped the polarized secretome
of quiescent endothelial cells, however, endothelial polarized secretion in pathological conditions
remains largely unknown.
Atherosclerosis is a severe cardiovascular disease and is a leading cause of death. It results
from chronic inflammation in the vascular wall characterised by the development of an
atherosclerotic plaque. In the late stages, the plaque narrows the bloodstream and is prone to
rupture, resulting in severe thrombosis or heart attack. There are few symptoms present in the
early stages of atherosclerosis, however, on the cellular level, early atherosclerosis causes severe
endothelial dysfunction, which is known to alter cellular properties such as secretion.
In this research, a proteomic screen was performed to map the polarized secretome of endothelial
cells exposed to lipoprotein, an early driver of atherosclerosis. Out of a deep secretome
identifying more than 1000 proteins, a cohort of 14 pro-inflammatory proteins was identified
whose secretions were increased in response to lipoproteins. A notable amount of the secreted
protein was Fibronectin, one of the proteomic targets and displayed significant alternation in
response to lipoproteins. The lipoproteins also drove the secretion of many other matrix components,
interestingly, LDL did not alter the gene expression level of the targets, which suggests its
impact on endothelial secretion is post-transcriptional. It has also been demonstrated that by
silencing LDLR, the major lipoprotein receptor in endothelial cells, the fibronectin secretion was
attenuated but not completely blocked, suggesting the actions of other receptors involved in LDL
signalling.
Overall, this research has uncovered the novel endothelial secretome in response to lipoprotein.
It has revealed that endothelial cells secrete a series of pro-inflammatory proteins, some of which
have been previously shown to contribute to the progression of the disease. These targets can be
the potential serum biomarkers used in the diagnosis of atherosclerosis.

Date of Award	5 Dec 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Harry H Mellor (Supervisor)