Ischemic vascular disease remains the leading cause of mortality in the developed world. Aldosterone (aldo) is a steroid hormone that acts by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor, to regulate blood pressure (bp). In clinical trials, aldo antagonists significantly decrease cardiovascular mortality and ischemia out of proportion to modest decreases in systemic bp, supporting that a direct vascular effect of aldo contributes to the protective role of aldo antagonists in ischemic cardiovascular disease. We recently discovered that MR is expressed and regulates gene transcription programs in human vascular smooth muscle cells (VSMC) and endothelial cells. In animal models of vascular injury and atherosclerosis, aldo infusion increases vascular remodeling and atherosclerosis. We now have preliminary data demonstrating that direct activation of MR in the aorta induces expression of the pro-atherosclerotic gene, placental growth factor (PlGF), and that genetic deficiency of PlGF in mice inhibits aldo-stimulated vascular injury suggesting that PlGF may play a role in the mechanism of aldo-mediated vascular disease. PlGF is a secreted peptide member of the vascular endothelial growth factor family and is known to promote vascular cell proliferation, monocyte chemotaxis, and inflammation by binding to the transmembrane receptor, fms-like tyrosine kinase (Flt-1). PlGF has been implicated in atherosclerosis and adverse ischemic events in animal models and in humans. In this proposal, we test the hypothesis that aldo activation of VSMC MR induces expression of PlGF, which activates Flt-1 receptors to stimulate VSMC proliferation, macrophage recruitment, vascular inflammation, and atherosclerotic plaque formation in vivo. We explore this hypothesis with three specific aims: SA1 uses molecular approaches to investigate the transcriptional regulation of the PlGF gene by vascular MR., SA2 investigates the in vivo role of PlGF in aldo-stimulated vascular injury using a wire-induced carotid injury model in mice, and SA3 investigates the in vivo role of PlGF in aldo-stimulated atherosclerosis in the ApoE knockout model. In these two mouse models, the mechanism by which PlGF mediates aldo-stimulated vascular disease will be explored by comparing mice genetically deficient in PlGF, mice with inducible VSMC-specific MR deletion, and mice overexpressing soluble Flt-1 receptors to block PlGF signaling. The in vivo role of PlGF transcriptional-regulatory pathways in aldo-stimulated injury and atherosclerosis will also be investigated using chromatin immunoprecipitation in vessels from these mouse models. A better understanding of the role of vascular MR induction of PlGF in vascular remodeling and atherosclerosis will help elucidate mechanisms underlying the vascular protective effects of aldo-antagonist drugs in cardiovascular patients and will explore the potential of PlGF and its signaling pathway as new drug targets to prevent cardiovascular ischemic events in humans.
Despite recent advances in our understanding of the pathophysiology of atherosclerosis, ischemic cardiovascular disease, which includes heart attack and stroke, remains the leading cause of death in the developed world. Clinical studies demonstrate that drugs that inhibit binding of the blood pressure-regulating hormone aldosterone to the mineralocorticoid receptor prevent ischemic events by unknown mechanisms. The overall goal of this proposal is to identify the genes that are regulated by mineralocorticoid receptors in the blood vessel and to explore the role of these genes in promoting vascular disease in order to identify new therapeutic targets to prevent and treat ischemic cardiovascular diseases.
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