Smooth Muscle Cell Mineralocorticoid Receptors Are Mandatory for Aldosterone–Salt to Induce Vascular Stiffness

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 63; no. 3; pp. 520 - 526
• Main Authors: Galmiche, Guillaume, Pizard, Anne, Gueret, Alexandre, El Moghrabi, Soumaya, Ouvrard-Pascaud, Antoine, Berger, Stefan, Challande, Pascal, Jaffe, Iris Z., Labat, Carlos, Lacolley, Patrick, Jaisser, Frédéric
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01-03-2014; Lippincott Williams & Wilkins
• Subjects: Aldosterone - toxicity; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Cardiology. Vascular system; Disease Models, Animal; Hypertension - chemically induced; Hypertension - metabolism; Hypertension - physiopathology; Male; Medical sciences; Mice; Mice, Transgenic; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - physiopathology; Receptors, Mineralocorticoid - metabolism; Signal Transduction; Sodium Chloride, Dietary - toxicity; Vascular Stiffness - drug effects; Mineralocorticoid; Smooth muscle; Cardiovascular disease; Aldosterone; Salt; integrins; Integrin; Blood vessel; Stiffness; Cell; Biological receptor; Hypertension; receptors; Steroid hormone; Rodentia; Cell adhesion molecule; carotid arteries; vascular stiffness; Artery; Vertebrata; Mammalia; mice, transgenic; Mouse; Animal; Carotid; Adrenal hormone; Circulatory system; receptors, mineralocorticoid; aldosterone
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.113.01967

Arterial stiffness is recognized as a risk factor for many cardiovascular diseases. Aldosterone via its binding to and activation of the mineralocorticoid receptors (MRs) is a main regulator of blood pressure by controlling renal sodium reabsorption. Although both clinical and experimental data indicate that MR activation by aldosterone is involved in arterial stiffening, the molecular mechanism is not known. In addition to the kidney, MR is expressed in both endothelial and vascular smooth muscle cells (VSMCs), but the specific contribution of the VSMC MR to aldosterone-induced vascular stiffness remains to be explored. To address this question, we generated a mouse model with conditional inactivation of the MR in VSMC (MR). MR mice show no alteration in renal sodium handling or vascular structure, but they have decreased blood pressure when compared with control littermate mice. In vivo at baseline, large vessels of mutant mice presented with normal elastic properties, whereas carotids displayed a smaller diameter when compared with those of the control group. As expected after aldosterone/salt challenge, the arterial stiffness increased in control mice; however, it remained unchanged in MR mice, without significant modification in vascular collagen/elastin ratio. Instead, we found that the fibronectin/α5-subunit integrin ratio is profoundly altered in MR mice because the induction of α5 expression by aldosterone/salt challenge is prevented in mice lacking VSMC MR. Altogether, our data reveal in the aldosterone/salt hypertension model that MR activation specifically in VSMC leads to the arterial stiffening by modulation of cell-matrix attachment proteins independent of major vascular structural changes.