Determinants of flow-mediated outward remodeling in female rodents: respective roles of age, estrogens, and timing.
OBJECTIVE
Flow (shear stress)-mediated outward remodeling (FMR) of resistance arteries is a key adaptive process allowing collateral growth after arterial occlusion but declining with age. 17-β-estradiol (E2) has a key role in this process through activation of estrogen receptor α (ERα). Thus, we investigated the impact of age and timing for estrogen efficacy on FMR.


RESULTS
Female rats, 3 to 18 months old, were submitted to surgery to increase blood flow locally in 1 mesenteric artery in vivo. High-flow and normal-flow arteries were collected 2 weeks later for in vitro analysis. Diameter increased by 27% in high-flow arteries compared with normal-flow arteries in 3-month-old rats. The amplitude of remodeling declined with age (12% in 18-month-old rats) in parallel with E2 blood level and E2 substitution failed restoring remodeling in 18-month-old rats. Ovariectomy of 3-, 9-, and 12-month-old rats abolished FMR, which was restored by immediate E2 replacement. Nevertheless, this effect of E2 was absent 9 months after ovariectomy. In this latter group, ERα and endothelial nitric oxide synthase expression were reduced by half compared with age-matched rats recently ovariectomized. FMR did not occur in ERα(-/-) mice, whereas it was decreased by 50% in ERα(+/-) mice, emphasizing the importance of gene dosage in high-flow remodeling.


CONCLUSIONS
E2 deprivation, rather than age, leads to decline in FMR, which can be prevented by early exogenous E2. However, delayed E2 replacement was ineffective on FMR, underlining the importance of timing of this estrogen action.
From the LUNAM (L'université Nantes, Le Mans et Angers) University and University of Angers, Angers, France (K.T., B.T., V.P., L.G., D.H.); Centre National de la Recherche Scientifique 6214, Angers, France (A.L.G., L.L., D.H.); Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Angers, France (D.H.); Centre Hospitalo-Universitaire d'Angers, Angers, France (E.V., V.P., D.H.); and INSERM U1048, Toulouse III Paul Sabatier University, CHU de Toulouse, Toulouse, France (F.L., J.F.A.).
Kahena
K
Tarhouni
From the LUNAM (L'université Nantes, Le Mans et Angers) University and University of Angers, Angers, France (K.T., B.T., V.P., L.G., D.H.); Centre National de la Recherche Scientifique 6214, Angers, France (A.L.G., L.L., D.H.); Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Angers, France (D.H.); Centre Hospitalo-Universitaire d'Angers, Angers, France (E.V., V.P., D.H.); and INSERM U1048, Toulouse III Paul Sabatier University, CHU de Toulouse, Toulouse, France (F.L., J.F.A.).
Anne-Laure
AL
Guihot
From the LUNAM (L'université Nantes, Le Mans et Angers) University and University of Angers, Angers, France (K.T., B.T., V.P., L.G., D.H.); Centre National de la Recherche Scientifique 6214, Angers, France (A.L.G., L.L., D.H.); Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Angers, France (D.H.); Centre Hospitalo-Universitaire d'Angers, Angers, France (E.V., V.P., D.H.); and INSERM U1048, Toulouse III Paul Sabatier University, CHU de Toulouse, Toulouse, France (F.L., J.F.A.).
Emilie
E
Vessières
From the LUNAM (L'université Nantes, Le Mans et Angers) University and University of Angers, Angers, France (K.T., B.T., V.P., L.G., D.H.); Centre National de la Recherche Scientifique 6214, Angers, France (A.L.G., L.L., D.H.); Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Angers, France (D.H.); Centre Hospitalo-Universitaire d'Angers, Angers, France (E.V., V.P., D.H.); and INSERM U1048, Toulouse III Paul Sabatier University, CHU de Toulouse, Toulouse, France (F.L., J.F.A.).
Bertrand
B
Toutain
From the LUNAM (L'université Nantes, Le Mans et Angers) University and University of Angers, Angers, France (K.T., B.T., V.P., L.G., D.H.); Centre National de la Recherche Scientifique 6214, Angers, France (A.L.G., L.L., D.H.); Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Angers, France (D.H.); Centre Hospitalo-Universitaire d'Angers, Angers, France (E.V., V.P., D.H.); and INSERM U1048, Toulouse III Paul Sabatier University, CHU de Toulouse, Toulouse, France (F.L., J.F.A.).
Vincent
V
Procaccio
From the LUNAM (L'université Nantes, Le Mans et Angers) University and University of Angers, Angers, France (K.T., B.T., V.P., L.G., D.H.); Centre National de la Recherche Scientifique 6214, Angers, France (A.L.G., L.L., D.H.); Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Angers, France (D.H.); Centre Hospitalo-Universitaire d'Angers, Angers, France (E.V., V.P., D.H.); and INSERM U1048, Toulouse III Paul Sabatier University, CHU de Toulouse, Toulouse, France (F.L., J.F.A.).
Linda
L
Grimaud
From the LUNAM (L'université Nantes, Le Mans et Angers) University and University of Angers, Angers, France (K.T., B.T., V.P., L.G., D.H.); Centre National de la Recherche Scientifique 6214, Angers, France (A.L.G., L.L., D.H.); Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Angers, France (D.H.); Centre Hospitalo-Universitaire d'Angers, Angers, France (E.V., V.P., D.H.); and INSERM U1048, Toulouse III Paul Sabatier University, CHU de Toulouse, Toulouse, France (F.L., J.F.A.).
Laurent
L
Loufrani
From the LUNAM (L'université Nantes, Le Mans et Angers) University and University of Angers, Angers, France (K.T., B.T., V.P., L.G., D.H.); Centre National de la Recherche Scientifique 6214, Angers, France (A.L.G., L.L., D.H.); Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Angers, France (D.H.); Centre Hospitalo-Universitaire d'Angers, Angers, France (E.V., V.P., D.H.); and INSERM U1048, Toulouse III Paul Sabatier University, CHU de Toulouse, Toulouse, France (F.L., J.F.A.).
Francoise
F
Lenfant
From the LUNAM (L'université Nantes, Le Mans et Angers) University and University of Angers, Angers, France (K.T., B.T., V.P., L.G., D.H.); Centre National de la Recherche Scientifique 6214, Angers, France (A.L.G., L.L., D.H.); Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Angers, France (D.H.); Centre Hospitalo-Universitaire d'Angers, Angers, France (E.V., V.P., D.H.); and INSERM U1048, Toulouse III Paul Sabatier University, CHU de Toulouse, Toulouse, France (F.L., J.F.A.).
Jean-Francois
JF
Arnal
From the LUNAM (L'université Nantes, Le Mans et Angers) University and University of Angers, Angers, France (K.T., B.T., V.P., L.G., D.H.); Centre National de la Recherche Scientifique 6214, Angers, France (A.L.G., L.L., D.H.); Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Angers, France (D.H.); Centre Hospitalo-Universitaire d'Angers, Angers, France (E.V., V.P., D.H.); and INSERM U1048, Toulouse III Paul Sabatier University, CHU de Toulouse, Toulouse, France (F.L., J.F.A.). daniel.henrion@univ-angers.fr.
Daniel
D
Henrion
D000375:Aging; D000818:Animals; D004730:Endothelium, Vascular / Q000502:physiology; D004958:Estradiol / Q000097:blood / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000032:analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D008638:Mesenteric Arteries / Q000473:pathology / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D010052:Ovariectomy; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D014655:Vascular Resistance; D014664:Vasodilation
D047628:Estrogen Receptor alpha; D004958:Estradiol; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D048049:Extracellular Signal-Regulated MAP Kinases
blood flow velocity; estrogens; ventricular remodeling