Sex Differences in Vascular Inflammation in Atherosclerosis and the Role of the Endothelial Mineralocorticoid Receptor
Atherosclerosis is a chronic disease in which cholesterol-containing plaques form in blood vessels. Inflammation of these plaques leads to their rupture and the formation of a blood clot which blocks blood flow to downstream tissues. This is the cause of nearly all heart attacks, ischemic strokes, and critical limb ischemia. Atherosclerosis affects more than one-third of the American population, and complications from atherosclerotic plaque rupture are the leading cause of death in the USA. Pre-menopausal women are resistant to the adverse cardiovascular events associated with atherosclerosis, but this protection diminishes rapidly with age after menopause, through currently unknown mechanisms.
Clinical data indicates that increased levels of the hormone aldosterone correlate with a greater incidence of heart attack, stroke and cardiovascular death. Aldosterone promotes sodium homeostasis by binding to and activating the mineralocorticoid receptor (MR) in the kidney. However, nearly all cells of the body, including those that make up the blood vessel wall, express the MR. The Jaffe Lab has previously shown that aldosterone administration to male mice promotes inflammation of atherosclerotic plaques, a phenotype associated with the plaque rupture in humans. However, whether vascular inflammation was due to vascular MR and the impact in females was unknown.
Elizabeth Moss, a senior Sackler MD/PhD student in the Jaffe Lab, is studying the role of the MR specifically in endothelial cells (ECs) in the development of vascular inflammation in atherosclerosis. ECs line the lumen of the blood vessel and serve as the first point of contact with inflammatory cells as they migrate into the atherosclerotic plaque. Elizabeth used a mouse model in which the MR is deleted specifically from ECs (EC-MR) compared to MR-intact littermates and exposed male and female mice to a virus that induces severe hyperlipidemia and atherosclerosis when combined with high fat diet for 12 weeks. Once the mice developed atherosclerosis, Elizabeth used flow cytometry to quantify the number and type of inflammatory cells within the diseased aortic arches from these mice.
Elizabeth discovered that female mice developed plaques with significantly less vascular inflammation than male littermates. Furthermore, in male mice EC-MR deletion reduced inflammation, but in female mice inflammation was not further effected by EC-MR deletion. These studies suggest a role for MR specifically in the vascular ECs in males in promoting inflammation, a factor that is associated with atherosclerotic plaque rupture in humans. In addition, the results raise the intriguing possibility that sex differences in EC-MR function may explain the protection from plaque rupture observed in pre-menopausal women. Elizabeth is currently conducting studies in female mice after surgery to remove their ovaries to investigate whether estrogen signaling interacts with EC-MR in female mice to influence vascular inflammation. These studies are beginning to answer important questions about how atherosclerotic plaques become inflamed with potential implications for the way atherosclerosis is treated clinically in men and women.
Moss ME, DuPont JJ, Iyer SL, McGraw AP, Jaffe IZ. 2018. No significant role for smooth muscle cell mineralocorticoid receptors in atherosclerosis in the apolipoprotein-E knockout mouse model. Front Cardiovasc Med. 5:81. Abstract
Moss ME, Jaffe IZ. 2015. Mineralocorticoid receptors in the pathophysiology of vascular inflammation and atherosclerosis. Front Endocrinol (Lausanne) 6: 153. Abstract