Increased arterial stiffness and premature wave reflections are important determinants of elevated systolic and pulse pressure and have been shown to predict cardiovascular morbidity and mortality, independent of coronary heart disease risk factors, in individuals with established disease and in the general population. Histopathological examination of large conduit vessels has shown that arterial stiffness is associated with architectural remodeling of the vessel media characterized by vascular smooth muscle cell disarray, increased deposition of aberrant collagen and fragmentation of elastin, all of which contribute to decrease a functional decrease in vascular compliance. It is also recognized that increased aorta stiffness, which exposes resistance vessels of the microvasculature to pulsatile flow, results in microvascular remodeling. In this manner, central arterial stiffness and concomitant microvascular dysfunction increases mean arterial pressure and, thereby, promotes systolic hypertension. It has been shown that these pathological and functional abnormalities are associated with minimally elevated levels of aldosterone, which is a highly prevalent finding, however, the cellular and molecular mechanism(s) by which aldosterone initiates central arterial stiffness remain unknown. There is accumulating evidence to suggest that an aldosterone-mediated activation of autophagy to induce vascular smooth muscle cell (VSMC) phenotype transition mediates the pathogenesis of arterial stiffness. We have shown previously that minimally elevated levels of aldosterone decrease the expression and activity of glucose-6-phosphate dehydrogenase (G6PD) to increase vascular oxidant stress and impair vascular reactivity. G6PD is the first and rate-limiting enzyme of the pentose phosphate pathway, is reversibly linked to glycolysis and mitochondrial respiration, and is the principal cytosolic source of NADPH, a reducing equivalent that is required to maintain redox homeostasis;when G6PD activity is deficient, cellular metabolism and redox state are perturbed leading to the activation of autophagy as a survival strategy. Under these conditions, activation of autophagy has been associated with cellular cytoskeletal rearrangement and phenotype transition. As the central theme of this proposal, we hypothesize that arterial stiffness results from and aldosterone-mediated acquired G6PD deficiency that activates autophagy to promote VSMC phenotype transition. To examine this hypothesis, we propose to: i) determine the molecular and cellular consequences of aldosterone-induced autophagy for VSMC phenotype, function, and extracellular matrix synthesis under conditions of pulsatile and non-pulsatile flow;ii) examine the effect of aldosterone-mediated G6PD deficiency and activation of autophagy on cellular metabolism, including glycolysis and mitochondrial function;iii) determine the efficacy of eplerenone, an aldosterone antagonist, G6PD overexpression, or modulating autophagy in limiting VSMC phenotype transition in vitro;iv) confirm these findings in vivo by examining the vascular morphological and functional changes of large conduit arteries and the microvasculature associated with aldosterone-induced autophagy in mouse models of G6PD deficiency, G6PD overexpression, and impaired autophagy (beclin ), and v) determine the temporal relationship between aldosterone-induced autophagy, arterial stiffness and microvascular remodeling, and hypertension. These findings will demonstrate that aldosterone promotes arterial stiffness by activating autophagy leading to VSMC phenotype transition and suggest further that aldosterone antagonists, interventions to increase G6PD activity, or autophagy modulators may have therapeutic benefit in patients with increased arterial stiffness.

Public Health Relevance

Arterial stiffness and wave reflections have been associated with adverse cardiovascular events and contribute to the development of systolic hypertension. Aldosterone-mediated G6PD deficiency and activation of autophagy to influence vascular smooth muscle cell phenotype is involved in the pathogenesis of arterial stiffening and microvascular remodeling. This highlights the central role of aldosterone, G6PD, and autophagy in arterial stiffness and identifies these mediators as therapeutic targets.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-W (S1))
Program Officer
OH, Youngsuk
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Leopold, Jane A (2015) Antioxidants and coronary artery disease: from pathophysiology to preventive therapy. Coron Artery Dis 26:176-83
Leopold, Jane A (2015) The Central Role of Neutrophil Gelatinase-Associated Lipocalin in Cardiovascular Fibrosis. Hypertension 66:20-2
Leopold, Jane A (2015) Vascular calcification: Mechanisms of vascular smooth muscle cell calcification. Trends Cardiovasc Med 25:267-74
Maron, Bradley A; Leopold, Jane A (2015) Emerging Concepts in the Molecular Basis of Pulmonary Arterial Hypertension: Part II: Neurohormonal Signaling Contributes to the Pulmonary Vascular and Right Ventricular Pathophenotype of Pulmonary Arterial Hypertension. Circulation 131:2079-91
Leopold, Jane A (2015) Obesity-related cardiomyopathy is an adipocyte-mediated paracrine disease. Trends Cardiovasc Med 25:127-8
Maron, Bradley A; Oldham, William M; Chan, Stephen Y et al. (2014) Upregulation of steroidogenic acute regulatory protein by hypoxia stimulates aldosterone synthesis in pulmonary artery endothelial cells to promote pulmonary vascular fibrosis. Circulation 130:168-79
Leopold, Jane A (2014) Microvascular dysfunction: genetic polymorphisms suggest sex-specific differences in disease phenotype. Coron Artery Dis 25:275-6
Leopold, Jane A (2014) MicroRNAs Regulate Vascular Medial Calcification. Cells 3:963-80
Leopold, Jane A (2014) Neoatherosclerosis: another consequence of endothelial dysfunction? Circ Cardiovasc Interv 7:635-7
Maron, Bradley A; Waxman, Aaron B; Opotowsky, Alexander R et al. (2013) Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] study 1 and 2 trials). Am J Cardiol 112:720-5

Showing the most recent 10 out of 28 publications