The Role of Vascular MR-Regulated Genes in Vascular Function and Disease

Summary

Principal Investigator: Iris Z Jaffe
Abstract: 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.
Funding Period: 2009-07-15 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion
    Massimiliano Caprio
    Department of Medicine Division of Cardiology, Tufts Medical Center and Tufts University School of Medicine, Boston, MA 02111, USA
    Circ Res 102:1359-67. 2008
  2. pmc Direct role for smooth muscle cell mineralocorticoid receptors in vascular remodeling: novel mechanisms and clinical implications
    Jenny B Koenig
    Sackler School of Graduate Biomedical Sciences at Tufts University School of Medicine, Boston, MA, USA
    Curr Hypertens Rep 16:427. 2014
  3. pmc Pre-eclampsia and cardiovascular disease
    Christina W Chen
    Division of Nephrology Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN 370D, Boston, MA 02215, USA
    Cardiovasc Res 101:579-86. 2014
  4. pmc Aldosterone promotes vascular remodeling by direct effects on smooth muscle cell mineralocorticoid receptors
    Dafina Pruthi
    From the Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA D P, A M, M A, C G, I Z J and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA S A K
    Arterioscler Thromb Vasc Biol 34:355-64. 2014
  5. pmc Smooth muscle cell mineralocorticoid receptors: role in vascular function and contribution to cardiovascular disease
    Amy McCurley
    Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA, USA
    Pflugers Arch 465:1661-70. 2013
  6. pmc Aldosterone increases early atherosclerosis and promotes plaque inflammation through a placental growth factor-dependent mechanism
    Adam P McGraw
    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
    J Am Heart Assoc 2:e000018. 2013
  7. pmc Mineralocorticoid receptor antagonism attenuates experimental pulmonary hypertension
    Ioana R Preston
    Tupper Research Institute and Pulmonary, Critical Care and Sleep Division, Tufts Medical Center, Boston, MA 02111, USA
    Am J Physiol Lung Cell Mol Physiol 304:L678-88. 2013
  8. pmc Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease?
    Shawn B Bender
    Department of Internal Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA
    Diabetes 62:313-9. 2013
  9. pmc Mineralocorticoid receptor antagonism inhibits vein graft remodeling in mice
    Afshin Ehsan
    Division of Cardiothoracic Surgery, Tufts Medical Center, Boston, Mass 02111, USA
    J Thorac Cardiovasc Surg 145:1642-9, 1649.e1. 2013
  10. pmc Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors
    Amy McCurley
    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
    Nat Med 18:1429-33. 2012

Detail Information

Publications18

  1. pmc Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion
    Massimiliano Caprio
    Department of Medicine Division of Cardiology, Tufts Medical Center and Tufts University School of Medicine, Boston, MA 02111, USA
    Circ Res 102:1359-67. 2008
    ..These studies describe a novel mechanism by which aldosterone may influence ischemic cardiovascular events and support a new explanation for the decrease in ischemic events in patients treated with aldosterone antagonists...
  2. pmc Direct role for smooth muscle cell mineralocorticoid receptors in vascular remodeling: novel mechanisms and clinical implications
    Jenny B Koenig
    Sackler School of Graduate Biomedical Sciences at Tufts University School of Medicine, Boston, MA, USA
    Curr Hypertens Rep 16:427. 2014
    ....
  3. pmc Pre-eclampsia and cardiovascular disease
    Christina W Chen
    Division of Nephrology Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN 370D, Boston, MA 02215, USA
    Cardiovasc Res 101:579-86. 2014
    ..Future studies should focus on strategies to prevent the progression of cardiovascular disease in women exposed to pre-eclampsia, thereby improving long-term cardiovascular health in women. ..
  4. pmc Aldosterone promotes vascular remodeling by direct effects on smooth muscle cell mineralocorticoid receptors
    Dafina Pruthi
    From the Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA D P, A M, M A, C G, I Z J and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA S A K
    Arterioscler Thromb Vasc Biol 34:355-64. 2014
    ..We now test the hypothesis that SMC mineralocorticoid receptors (MRs) directly mediate the remodeling effects of aldosterone and further explore the mechanism...
  5. pmc Smooth muscle cell mineralocorticoid receptors: role in vascular function and contribution to cardiovascular disease
    Amy McCurley
    Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA, USA
    Pflugers Arch 465:1661-70. 2013
    ..Further exploration of the molecular mechanisms for the effects of SMC MR activation has the potential to identify novel therapeutic targets to prevent or treat common cardiovascular disorders. ..
  6. pmc Aldosterone increases early atherosclerosis and promotes plaque inflammation through a placental growth factor-dependent mechanism
    Adam P McGraw
    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
    J Am Heart Assoc 2:e000018. 2013
    ..Aldosterone levels correlate with the incidence of myocardial infarction and mortality in cardiovascular patients. Aldosterone promotes atherosclerosis in animal models, but the mechanisms are poorly understood...
  7. pmc Mineralocorticoid receptor antagonism attenuates experimental pulmonary hypertension
    Ioana R Preston
    Tupper Research Institute and Pulmonary, Critical Care and Sleep Division, Tufts Medical Center, Boston, MA 02111, USA
    Am J Physiol Lung Cell Mol Physiol 304:L678-88. 2013
    ..These data suggest that MR is involved in the pathogenesis of PH via effects on PASMCs and that MR antagonism may represent a novel therapeutic target for this disease...
  8. pmc Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease?
    Shawn B Bender
    Department of Internal Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA
    Diabetes 62:313-9. 2013
    ....
  9. pmc Mineralocorticoid receptor antagonism inhibits vein graft remodeling in mice
    Afshin Ehsan
    Division of Cardiothoracic Surgery, Tufts Medical Center, Boston, Mass 02111, USA
    J Thorac Cardiovasc Surg 145:1642-9, 1649.e1. 2013
    ..We demonstrated recently that the MR is upregulated in venous tissues after grafting and hypothesized that MR inhibition would reduce vein graft remodeling...
  10. pmc Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors
    Amy McCurley
    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
    Nat Med 18:1429-33. 2012
    ..This study identifies a new role for vascular MR in blood pressure control and in vascular aging and supports the emerging hypothesis that vascular tone contributes directly to systemic blood pressure...
  11. pmc Distinct effects of unfractionated heparin versus bivalirudin on circulating angiogenic peptides
    Navin K Kapur
    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America
    PLoS ONE 7:e34344. 2012
    ....
  12. pmc Mineralocorticoid receptors in vascular function and disease
    Amy McCurley
    Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA
    Mol Cell Endocrinol 350:256-65. 2012
    ..Further exploration of the molecular mechanisms for the detrimental vascular effects of MR activation has the potential to identify novel therapeutic targets to prevent or treat common cardiovascular disorders...
  13. pmc Aldosterone regulates vascular gene transcription via oxidative stress-dependent and -independent pathways
    Brenna G Newfell
    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
    Arterioscler Thromb Vasc Biol 31:1871-80. 2011
    ..Here we define the early Aldo-regulated vascular transcriptome and investigate the mechanisms of gene regulation by Aldo in the vasculature that may contribute to vascular disease...
  14. pmc Mineralocorticoid receptor expression in human venous smooth muscle cells: a potential role for aldosterone signaling in vein graft arterialization
    Richard Bafford
    Div of Vascular and Endovascular Surgery, Univ of California San Francisco, 400 Parnassus Ave, Ste A581, San Francisco, CA 94143 0222, USA
    Am J Physiol Heart Circ Physiol 301:H41-7. 2011
    ..The upregulation of MR and 11╬▓HSD2 suggests that aldosterone-mediated tissue injury plays a role in vein graft arterialization...
  15. pmc Placental growth factor mediates aldosterone-dependent vascular injury in mice
    Iris Z Jaffe
    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA
    J Clin Invest 120:3891-900. 2010
    ....

Research Grants30

  1. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
    ..abstract_text> ..
  2. Role of Eosinophils in Airway Inflammation and Remodeling
    Nizar N Jarjour; Fiscal Year: 2013
    ..Given the prominence of eosinophilic inflammation in a significant proportion of severe asthma patients, these advances will have direct implications for the patients most affected by this very common illness. ..
  3. Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells
    Rama Natarajan; Fiscal Year: 2013
    ..The results can increase our understanding of Ang II actions, and identify new targets that might be developed as clinical therapies for CVDs such as hypertension and atherosclerosis. ..
  4. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  5. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  6. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  7. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  8. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  9. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  10. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  11. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
  12. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
    ..abstract_text> ..
  13. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  14. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..