Mineralocorticoid receptor involvement in vascular dysfunction associated with vascular injury
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Mineralocorticoid receptor (MR) signaling has recently been implicated in cardiovascular dysfunction associated vascular injury. Specifically, MR blockade has been shown to treat coronary microvascular dysfunction in obesity and has been implicated in the regulation of capillary density in ischemic conditions. The fundamental mechanisms underlying these effects of MR signaling, as well as cell-specific MR involvement, in dysfunction associated with vascular injury remain poorly understood. This thesis tested the hypothesis that MR signaling impairs coronary microvascular function in diabetes and serves an anti-angiogenic role in ischemic tissue. Assessment of MR signaling in diabetes-related coronary dysfunction and the underlying MR-dependent vascular transcriptome was investigated using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat which recapitulates late-stage diabetes. MR inhibition with spironolactone treatment improved coronary endothelium-dependent vasodilation in OLETF rats. Further, RNA sequencing of aortas from Spironolactone-treated OLETF rats revealed 157 differentially expressed genes predicting MR involvement in angiogenesis, migration of endothelial cells (EC), and differentiation of smooth muscle cells. These biological functions are critical for the vascular response to flow deficit; thus we further assessed the fundamental role of MR in the vascular response to unilateral femoral artery excision. Here, femoral excision was performed in C57BL/6J mice treated with either vehicle or spironolactone as well as EC MR knockout (KO) or MR intact controls. Serial assessment of hindlimb perfusion over 28 days revealed that spironolactone and EC MR KO enhanced perfusion in female, but not, male mice. Assessment of peripheral collateral vasculature by micro-computed tomography revealed enhanced collateral expansion by spironolactone and EC MR KO in female, but not, male mice at 28 days. Finally, collateral expansion 7 days post-surgery was enhanced in both male and female EC MR KO mice associated with an increase in CD68+ (pan macrophage) and CD206+ (M2-like) macrophages in the collateral zone (area between femoral artery and internal iliac artery) of only female mice. In conclusion, these studies demonstrate a benefit of MR blockade in diabetes-associated coronary dysfunction and define, for the first time, a fundamental role of EC MR signaling to constrain arteriogenic collateralization in females.
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Ph. D.