Diabetes impairs the vascular effects of aldosterone mediated by G protein-coupled estrogen receptor activation.

Aldosterone promotes non-genomic effects in endothelial and vascular smooth muscle cells via activation of mineralocorticoid receptors (MR) and G protein-coupled estrogen receptors (GPER). GPER activation is associated with beneficial/protective effects in the vasculature. Considering that vascular dysfunction plays a major role in diabetes-associated complications, we hypothesized that the beneficial effects mediated by vascular GPER activation, in response to aldosterone, are decreased in diabetes. Mesenteric resistance arteries from female, 14-16 weeks-old, control and diabetic (db/db) mice were used. Phenylephrine (PhE)-induced contractions were greater in arteries from db/db vs. control mice. Aldosterone (10 nM) increased maximal contractile responses to PhE in arteries from control mice, an effect elicited via activation of GPER. Although aldosterone did not increase PhE responses in arteries from db/db mice, blockade of GPER and MR decreased PhE-induced contractile responses in db/db mesenteric arteries. Aldosterone also reduced the potency of acetylcholine (ACh)-induced relaxation in arteries from both control and db/db mice via MR-dependent mechanisms. GPER antagonism further decreased ACh-induced relaxation in the control group, but did not affect ACh responses in the diabetic group. Aldosterone increased extracellular signal-regulated kinase (ERK)1/2 phosphorylation in arteries from control and db/db mice by a GPER-dependent mechanism. GPER, but not MR, gene and protein expression, determined by RT-PCR and immunoblotting/immunofluorescence assays respectively, were increased in arteries from db/db mice vs. control arteries. These findings indicate that aldosterone activates both vascular MR and GPER and that the beneficial effects of GPER activation are decreased in arteries from diabetic animals. Our results further elucidate the mechanisms by which aldosterone influences vascular function and contributes to vascular dysfunction in diabetes

Systolic arterial pressure, body weight and echocardiographic data.

<p>Data are expressed as mean ± standard deviation of mean or median with 25 and 75 percentiles. n: number of rats. C: control group (no supplementation with vitamin D); VD3: supplemented with 3,000 IU VD/kg of chow; VD10: supplemented with 10,000 IU VD/kg of chow. BW: body weight; SAP: Systolic arterial pressure; HR: heart rate; CO: cardiac output; EF: ejection fraction; E: E wave; A: A wave; LA: left atrium; LVEDD: left ventricular (LV) end-diastolic diameter; LVM: left ventricular mass. * p<0.05 versus control group.</p

Summary of pD₂ and Maximal Response values.

<p>Data are expressed as mean ± standard deviation of mean or median with 25 and 75 percentiles; numbers in parentheses indicate the numbers of animals included in each experimental group. C: control group (no supplementation with vitamin D); VD3: supplemented with 3,000 IU VD/kg of chow; VD10: supplemented with 10,000 IU VD/kg of chow. pD₂: indicates -log EC₅₀ (the concentration of agonist producing half-maximal response); Phe: phenylephrine; E⁺: endothelium-intact vessels; E⁻: endothelium-denuded vessels; Ach: acetylcholine; SNP: sodium nitroprusside. * p<0.05 versus control group.</p

Data on the vascular mechanical properties and Metalloproteinase-2 and -9 activities by gelatin zimography.

<p>Data are expressed as mean ± standard deviation of mean or median with 25 and 75 percentiles, numbers in parentheses indicate the numbers of animals included in each experimental group. C: control group (no supplementation with vitamin D); VD3: supplemented with 3,000 IU VD/kg of chow; VD10: supplemented with 10,000 IU VD/kg of chow. * p<0.05 versus control group; # p<0.05 versus VD3 group.</p

Elastin content in the aortic sections and fragmentation of elastic fibers in the VD10 group.

<p>Photographs of aortic samples (400×) stained by Calleja. C: control group (no supplementation with vitamin D); VD3: supplemented with 3,000 IU VD/kg of chow; VD10: supplemented with 10,000 IU VD/kg of chow.</p

Vitamin D and food ingestion, serum calcium and phosphorus and plasma 25 (OH) D₃.

<p>Data are expressed as mean ± standard deviation of mean or median with 25 and 75 percentiles, numbers in parentheses indicate the numbers of animals included in each experimental group. C: control group (no supplementation with vitamin D); VD3: supplemented with 3,000 IU VD/kg of chow; VD10: supplemented with 10,000 IU VD/kg of chow; 25 (OH) D₃: plasma 25-hydroxycholecalciferol; Ca: serum calcium; P: serum phosphorus. * p<0.05 versus control group; # p<0.05 versus VD3 group.</p