The Sex- and Cell Type-Specific Roles of Vascular Mineralocorticoid Receptors in Regulating Vascular Inflammation in Atherosclerosis.
Moss, M. Elizabeth.
2019
-
BACKGROUND: Atherosclerosis is a common vascular pathology in
which inflamed, lipid-laden plaques accumulate in the arteries. These
plaques can rupture and cause myocardial infarction and ischemic stroke,
making atherosclerosis the leading contributor to death worldwide.
Inflammation of atherosclerotic plaques increases the likelihood of rupture;
therefore, it is critical to understand the ... read moremechanisms that promote plaque
inflammation. Animal studies implicate the aldosterone-binding
mineralocorticoid receptor (MR) in atherosclerotic lesion formation and
inflammation, and clinical data reveals a correlation between aldosterone
levels and the incidence of cardiovascular ischemia, but the majority of
this work has been performed in male animals or in mostly-male cohorts.
Premenopausal women are protected from cardiovascular ischemia relative to
age-matched men, but this protection is lost after menopause. The molecular
mechanism for this phenomenon is poorly understood, with the current
literature suggesting that factors in addition to sex hormones may be
involved. OBJECTIVE: To investigate the mechanism for the contribution of
the MR to vascular inflammation in atherosclerosis by characterizing the
role of the MR within vascular smooth muscle cells (SMCs) and endothelial
cells (ECs) in atherosclerotic lesion formation and vascular inflammation in
males and females. METHODS & RESULTS: Histologic analysis of
atherosclerotic plaques, flow cytometry of the aortic arch to quantify
inflammatory cells, and intravital microscopy of the mesenteric vasculature
to visualize leukocyte-endothelial interactions were performed in
atherogenic mice with SMC- or EC-specific MR deletion. SMC-MR deletion did
not significantly alter plaque formation, morphology, or inflammation in
males. Conversely, EC-MR deletion attenuated vascular inflammation and
reduced leukocyte slow rolling and firm adhesion to the mesenteric
vasculature in males but not females, who were protected from inflammation
relative to males. This correlated with in vitro studies in human and mouse
ECs: MR inhibition reduced the expression of E-selectin and ICAM-1,
endothelial adhesion molecules that mediate leukocyte slow rolling and firm
adhesion, but not with estrogen co-administration. CONCLUSIONS: The MR
within vascular ECs drives inflammation of atherosclerotic plaques in a
sex-specific manner, potentially promoting susceptibility to rupture in men.
These results suggest that blockade of EC-MR or its downstream targets could
be an effective therapy to prevent plaque rupture while providing a novel
mechanism for the sex differences observed in cardiovascular ischemia in
humans.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Cell, Molecular & Developmental Biology.
Advisor: Iris Jaffe.
Committee: John Castellot, Pilar Alcaide, Athan Kuliopulos, and Andrew Lichtman.
Keywords: Physiology, Cellular biology, and Molecular biology.read less - ID:
- 8c97m316j
- To Cite:
- TARC Citation Guide EndNote