title: Smooth muscle cell mineralocorticoid receptors are mandatory for aldosterone-salt to induce vascular stiffness.
abstract: 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(SMKO)). MR(SMKO) 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(SMKO) mice, without significant modification in vascular collagen/elastin ratio. Instead, we found that the fibronectin/α5-subunit integrin ratio is profoundly altered in MR(SMKO) 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.
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie, Inserm U872 Équipe 1, Paris, France (G.G., S.E.M., F.J.); Inserm U1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France (A.P., C.L., P.L.); Inserm U1096, Rouen, France (A.G., A.O.-P.); German Cancer Research Center, Heidelberg, Germany (S.B.); Université Pierre et Marie Curie, Paris 06, France (P.C.); CNRS, UMR 7190, Paris, France (P.C.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Centre for Clinical Investigation, Inserm U9501, CHU Brabois, Vandoeuvre-lès-Nancy, France (A.P., F.J.).
authors.forename: Guillaume
authors.initials: G
authors.lastname: Galmiche
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie, Inserm U872 Équipe 1, Paris, France (G.G., S.E.M., F.J.); Inserm U1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France (A.P., C.L., P.L.); Inserm U1096, Rouen, France (A.G., A.O.-P.); German Cancer Research Center, Heidelberg, Germany (S.B.); Université Pierre et Marie Curie, Paris 06, France (P.C.); CNRS, UMR 7190, Paris, France (P.C.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Centre for Clinical Investigation, Inserm U9501, CHU Brabois, Vandoeuvre-lès-Nancy, France (A.P., F.J.).
authors.forename: Anne
authors.initials: A
authors.lastname: Pizard
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie, Inserm U872 Équipe 1, Paris, France (G.G., S.E.M., F.J.); Inserm U1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France (A.P., C.L., P.L.); Inserm U1096, Rouen, France (A.G., A.O.-P.); German Cancer Research Center, Heidelberg, Germany (S.B.); Université Pierre et Marie Curie, Paris 06, France (P.C.); CNRS, UMR 7190, Paris, France (P.C.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Centre for Clinical Investigation, Inserm U9501, CHU Brabois, Vandoeuvre-lès-Nancy, France (A.P., F.J.).
authors.forename: Alexandre
authors.initials: A
authors.lastname: Gueret
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie, Inserm U872 Équipe 1, Paris, France (G.G., S.E.M., F.J.); Inserm U1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France (A.P., C.L., P.L.); Inserm U1096, Rouen, France (A.G., A.O.-P.); German Cancer Research Center, Heidelberg, Germany (S.B.); Université Pierre et Marie Curie, Paris 06, France (P.C.); CNRS, UMR 7190, Paris, France (P.C.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Centre for Clinical Investigation, Inserm U9501, CHU Brabois, Vandoeuvre-lès-Nancy, France (A.P., F.J.).
authors.forename: Soumaya
authors.initials: S
authors.lastname: El Moghrabi
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie, Inserm U872 Équipe 1, Paris, France (G.G., S.E.M., F.J.); Inserm U1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France (A.P., C.L., P.L.); Inserm U1096, Rouen, France (A.G., A.O.-P.); German Cancer Research Center, Heidelberg, Germany (S.B.); Université Pierre et Marie Curie, Paris 06, France (P.C.); CNRS, UMR 7190, Paris, France (P.C.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Centre for Clinical Investigation, Inserm U9501, CHU Brabois, Vandoeuvre-lès-Nancy, France (A.P., F.J.).
authors.forename: Antoine
authors.initials: A
authors.lastname: Ouvrard-Pascaud
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie, Inserm U872 Équipe 1, Paris, France (G.G., S.E.M., F.J.); Inserm U1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France (A.P., C.L., P.L.); Inserm U1096, Rouen, France (A.G., A.O.-P.); German Cancer Research Center, Heidelberg, Germany (S.B.); Université Pierre et Marie Curie, Paris 06, France (P.C.); CNRS, UMR 7190, Paris, France (P.C.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Centre for Clinical Investigation, Inserm U9501, CHU Brabois, Vandoeuvre-lès-Nancy, France (A.P., F.J.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Berger
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie, Inserm U872 Équipe 1, Paris, France (G.G., S.E.M., F.J.); Inserm U1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France (A.P., C.L., P.L.); Inserm U1096, Rouen, France (A.G., A.O.-P.); German Cancer Research Center, Heidelberg, Germany (S.B.); Université Pierre et Marie Curie, Paris 06, France (P.C.); CNRS, UMR 7190, Paris, France (P.C.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Centre for Clinical Investigation, Inserm U9501, CHU Brabois, Vandoeuvre-lès-Nancy, France (A.P., F.J.).
authors.forename: Pascal
authors.initials: P
authors.lastname: Challande
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie, Inserm U872 Équipe 1, Paris, France (G.G., S.E.M., F.J.); Inserm U1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France (A.P., C.L., P.L.); Inserm U1096, Rouen, France (A.G., A.O.-P.); German Cancer Research Center, Heidelberg, Germany (S.B.); Université Pierre et Marie Curie, Paris 06, France (P.C.); CNRS, UMR 7190, Paris, France (P.C.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Centre for Clinical Investigation, Inserm U9501, CHU Brabois, Vandoeuvre-lès-Nancy, France (A.P., F.J.).
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie, Inserm U872 Équipe 1, Paris, France (G.G., S.E.M., F.J.); Inserm U1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France (A.P., C.L., P.L.); Inserm U1096, Rouen, France (A.G., A.O.-P.); German Cancer Research Center, Heidelberg, Germany (S.B.); Université Pierre et Marie Curie, Paris 06, France (P.C.); CNRS, UMR 7190, Paris, France (P.C.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Centre for Clinical Investigation, Inserm U9501, CHU Brabois, Vandoeuvre-lès-Nancy, France (A.P., F.J.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Labat
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie, Inserm U872 Équipe 1, Paris, France (G.G., S.E.M., F.J.); Inserm U1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France (A.P., C.L., P.L.); Inserm U1096, Rouen, France (A.G., A.O.-P.); German Cancer Research Center, Heidelberg, Germany (S.B.); Université Pierre et Marie Curie, Paris 06, France (P.C.); CNRS, UMR 7190, Paris, France (P.C.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Centre for Clinical Investigation, Inserm U9501, CHU Brabois, Vandoeuvre-lès-Nancy, France (A.P., F.J.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacolley
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie, Inserm U872 Équipe 1, Paris, France (G.G., S.E.M., F.J.); Inserm U1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France (A.P., C.L., P.L.); Inserm U1096, Rouen, France (A.G., A.O.-P.); German Cancer Research Center, Heidelberg, Germany (S.B.); Université Pierre et Marie Curie, Paris 06, France (P.C.); CNRS, UMR 7190, Paris, France (P.C.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Centre for Clinical Investigation, Inserm U9501, CHU Brabois, Vandoeuvre-lès-Nancy, France (A.P., F.J.).
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jaisser
mesh_terms: D000450:Aldosterone / Q000633:toxicity; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D015398:Signal Transduction; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D059289:Vascular Stiffness / Q000187:drug effects*
chemical_list: D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D000450:Aldosterone
keywords: aldosterone; carotid arteries; integrins; mice, transgenic; receptors, mineralocorticoid; vascular stiffness