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Placental growth factor mediates aldosterone-dependent vascular injury in mice
Iris Z. Jaffe, … , Afshin Ehsan, Michael E. Mendelsohn
Iris Z. Jaffe, … , Afshin Ehsan, Michael E. Mendelsohn
Published October 1, 2010
Citation Information: J Clin Invest. 2010;120(11):3891-3900. https://doi.org/10.1172/JCI40205.
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Research Article Cardiology

Placental growth factor mediates aldosterone-dependent vascular injury in mice

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Abstract

In clinical trials, aldosterone antagonists reduce cardiovascular ischemia and mortality by unknown mechanisms. Aldosterone is a steroid hormone that signals through renal mineralocorticoid receptors (MRs) to regulate blood pressure. MRs are expressed and regulate gene transcription in human vascular cells, suggesting that aldosterone might have direct vascular effects. Using gene expression profiling, we identify the pro-proliferative VEGF family member placental growth factor (PGF) as an aldosterone-regulated vascular MR target gene in mice and humans. Aldosterone-activated vascular MR stimulated Pgf gene transcription and increased PGF protein expression and secretion in the mouse vasculature. In mouse vessels with endothelial damage and human vessels from patients with atherosclerosis, aldosterone enhanced expression of PGF and its receptor, FMS-like tyrosine kinase 1 (Flt1). In atherosclerotic human vessels, MR antagonists inhibited PGF expression. In vivo, aldosterone infusion augmented vascular remodeling in mouse carotids following wire injury, an effect that was lost in Pgf–/– mice. In summary, we have identified PGF as what we believe to be a novel downstream target of vascular MR that mediates aldosterone augmentation of vascular injury. These findings suggest a non-renal mechanism for the vascular protective effects of aldosterone antagonists in humans and support targeting the vascular aldosterone/MR/PGF/Flt1 pathway as a therapeutic strategy for ischemic cardiovascular disease.

Authors

Iris Z. Jaffe, Brenna G. Newfell, Mark Aronovitz, Najwa N. Mohammad, Adam P. McGraw, Roger E. Perreault, Peter Carmeliet, Afshin Ehsan, Michael E. Mendelsohn

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Figure 1

PGF expression is regulated by aldosterone via vascular MR activation.

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PGF expression is regulated by aldosterone via vascular MR activation.
M...
Mouse aortas (A–C) or carotid arteries (D) were treated ex vivo with vehicle (white bars), aldosterone (black bars, 100 nM unless otherwise indicated), or aldosterone + spironolactone (gray bars, 10 μM spironolactone) for the indicated times. (A–C) Pgf mRNA expression was quantified by QRT-PCR of vessel RNA (A), Pgf protein was quantified by ELISA in vessel lysate (B), and secretion was quantified by ELISA of vessel conditioned media (C). (D) Carotid Pgf mRNA (left) and secreted protein (right) were quantified. #P < 0.05, ##P < 0.001 versus vehicle and aldosterone + spironolactone. *P < 0.05, **P < 0.01, ***P < 0.001 versus vehicle.
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