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Aldosterone-Induced Vascular Remodeling and Endothelial Dysfunction Require Functional Angiotensin Type 1a Receptors.

ABSTRACT: We investigated the role of angiotensin type 1a receptors (AGTR1a) in vascular injury induced by aldosterone activation of mineralocorticoid receptors in Agtr1a(-/-) and wild-type (WT) mice infused with aldosterone for 14 days while receiving 1% NaCl in drinking water. Aldosterone increased systolic blood pressure (BP) by ?30 mm Hg in WT mice and ?50 mm Hg in Agtr1a(-/-) mice. Aldosterone induced aortic and small artery remodeling, impaired endothelium-dependent relaxation in WT mice, and enhanced fibronectin and collagen deposition and vascular inflammation. None of these vascular effects were observed in Agtr1a(-/-) mice. Aldosterone effects were prevented by the AGTR1 antagonist losartan in WT mice. In contrast to aldosterone, norepinephrine caused similar BP increase and mesenteric artery remodeling in WT and Agtr1a(-/-) mice. Agtr1a(-/-) mice infused with aldosterone did not increase sodium excretion in response to a sodium chloride challenge, suggesting that sodium retention could contribute to the exaggerated BP rise induced by aldosterone. Agtr1a(-/-) mice had decreased mesenteric artery expression of the calcium-activated potassium channel Kcnmb1, which may enhance myogenic tone and together with sodium retention, exacerbate BP responses to aldosterone/salt in Agtr1a(-/-) mice. We conclude that although aldosterone activation of mineralocorticoid receptors raises BP more in Agtr1a(-/-) mice, AGTR1a is required for mineralocorticoid receptor stimulation to induce vascular remodeling and inflammation and endothelial dysfunction.

SUBMITTER: Briet M

PROVIDER: S-EPMC4833572 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Aldosterone-Induced Vascular Remodeling and Endothelial Dysfunction Require Functional Angiotensin Type 1a Receptors.

Briet Marie M Barhoumi Tlili T Mian Muhammad Oneeb Rehman MOR Coelho Suellen C SC Ouerd Sofiane S Rautureau Yohann Y Coffman Thomas M TM Paradis Pierre P Schiffrin Ernesto L EL

Hypertension (Dallas, Tex. : 1979) 20160404 5

We investigated the role of angiotensin type 1a receptors (AGTR1a) in vascular injury induced by aldosterone activation of mineralocorticoid receptors in Agtr1a(-/-) and wild-type (WT) mice infused with aldosterone for 14 days while receiving 1% NaCl in drinking water. Aldosterone increased systolic blood pressure (BP) by ≈30 mm Hg in WT mice and ≈50 mm Hg in Agtr1a(-/-) mice. Aldosterone induced aortic and small artery remodeling, impaired endothelium-dependent relaxation in WT mice, and enhanc ...[more]

PMID: 27045029

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Project description: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.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.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.

Dataset Information

Aldosterone-Induced Vascular Remodeling and Endothelial Dysfunction Require Functional Angiotensin Type 1a Receptors.

Publications

Aldosterone-Induced Vascular Remodeling and Endothelial Dysfunction Require Functional Angiotensin Type 1a Receptors.

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