Aldosterone promotes vascular remodeling by direct effects on smooth muscle cell mineralocorticoid receptors.

Abstract

OBJECTIVE:

Vascular remodeling occurs after endothelial injury, resulting in smooth muscle cell (SMC) proliferation and vascular fibrosis. We previously demonstrated that the blood pressure-regulating hormone aldosterone enhances vascular remodeling in mice at sites of endothelial injury in a placental growth factor-dependent manner. We now test the hypothesis that SMC mineralocorticoid receptors (MRs) directly mediate the remodeling effects of aldosterone and further explore the mechanism.

APPROACH AND RESULTS:

A wire-induced carotid injury model was performed in wild-type mice and mice with inducible SMC-specific deletion of the MR. Aldosterone did not affect re-endothelialization after injury in wild-type mice. Deletion of SMC-MR prevented the 79% increase in SMC proliferation induced by aldosterone after injury in MR-Intact littermates. Moreover, both injury-induced and aldosterone-enhanced vascular fibrosis were attenuated in SMC-specific MR knockout mice. Further exploration of the mechanism revealed that aldosterone-induced vascular remodeling is prevented by in vivo blockade of the placental growth factor-specific receptor, type 1 vascular endothelial growth factor receptor (VEGFR1), the receptor for placental growth factor. Immunohistochemistry of carotid vessels shows that the induction of VEGFR1 expression in SMC after vascular injury is attenuated by 72% in SMC-specific MR knockout mice. Moreover, aldosterone induction of vascular placental growth factor mRNA expression and protein release are also prevented in vessels lacking SMC-MR.

CONCLUSIONS:

These studies reveal that SMC-MR is necessary for aldosterone-induced vascular remodeling independent of renal effects on blood pressure. SMC-MR contributes to induction of SMC VEGFR1 in the area of vascular injury and to aldosterone-enhanced vascular placental growth factor expression and hence the detrimental effects of aldosterone are prevented by VEGFR1 blockade. This study supports exploring MR antagonists and VEGFR1 blockade to prevent pathological vascular remodeling induced by aldosterone.

• Authors: Dafina Pruthi, Amy McCurley, Mark Aronovitz, Carol Galayda, S Ananth Karumanchi, Iris Z Jaffe
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 34 Issue 2 Pg. 355-64 (Feb 2014) ISSN: 1524-4636 [Electronic] United States
• PMID: 24311380 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Pgf protein, mouse
• Pregnancy Proteins
• RNA, Messenger
• Receptors, Mineralocorticoid
• Placenta Growth Factor
• Aldosterone
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Aldosterone (pharmacology)
• Animals
• Antibodies (pharmacology)
• Carotid Arteries (drug effects, metabolism, pathology)
• Carotid Artery Injuries (genetics, metabolism, pathology)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Endothelial Cells (drug effects, metabolism, pathology)
• Fibrosis
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
• Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
• Placenta Growth Factor
• Pregnancy Proteins (genetics, metabolism)
• RNA, Messenger (metabolism)
• Receptors, Mineralocorticoid (agonists, deficiency, genetics)
• Time Factors
• Vascular Endothelial Growth Factor Receptor-1 (antagonists & inhibitors, metabolism)