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Aldosterone promotes vascular remodeling by direct effects on smooth muscle cell mineralocorticoid receptors. 2014

Dafina Pruthi, and Amy McCurley, and Mark Aronovitz, and Carol Galayda, and S Ananth Karumanchi, and Iris Z Jaffe
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.).

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. 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.

UI MeSH Term Description Entries
D008297 Male Males
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D009131 Muscle, Smooth, Vascular The nonstriated involuntary muscle tissue of blood vessels. Vascular Smooth Muscle,Muscle, Vascular Smooth,Muscles, Vascular Smooth,Smooth Muscle, Vascular,Smooth Muscles, Vascular,Vascular Smooth Muscles
D011257 Pregnancy Proteins Proteins produced by organs of the mother or the PLACENTA during PREGNANCY. These proteins may be pregnancy-specific (present only during pregnancy) or pregnancy-associated (present during pregnancy or under other conditions such as hormone therapy or certain malignancies.) Placental Proteins,Proteins, Placental,Proteins, Pregnancy
D002339 Carotid Arteries Either of the two principal arteries on both sides of the neck that supply blood to the head and neck; each divides into two branches, the internal carotid artery and the external carotid artery. Arteries, Carotid,Artery, Carotid,Carotid Artery
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D005355 Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Cirrhosis,Fibroses
D000072483 Placenta Growth Factor An angiogenic protein belonging to the Vascular Endothelial Growth Factor family of growth factors originally isolated and cloned from human placental cDNA library. There are four isoforms of PLGF 1-4 which result from alternative splicing. Placenta Growth Factor is secreted as a glycosylated homodimer which acts as a mitogen for endothelial cells, and its expression is markedly upregulated during hypoxia and in tissue inflammation and cancer. Placenta Growth Factor, PLGF-1 Isoform,Placenta Growth Factor, PLGF-2 Isoform,Placenta Growth Factor, PLGF-3 Isoform,Placenta Growth Factor, PLGF-4 Isoform,Factor, Placenta Growth,Growth Factor, Placenta,Placenta Growth Factor, PLGF 1 Isoform,Placenta Growth Factor, PLGF 2 Isoform,Placenta Growth Factor, PLGF 3 Isoform,Placenta Growth Factor, PLGF 4 Isoform
D000450 Aldosterone A hormone secreted by the ADRENAL CORTEX that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Aldosterone, (+-)-Isomer,Aldosterone, (11 beta,17 alpha)-Isomer
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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