Cyclooxygenase-2 preserves flow-mediated remodelling in old obese Zucker rat mesenteric arteries

AIMS: Resistance arteries have a key role in the control of local blood flow and pressure, and chronic increases in blood flow induce endothelium-dependent outward hypertrophic remodelling. The incidence of metabolic syndrome increases with age, and the combination of these two risk factors impairs endothelium integrity, in part through an inflammatory process. We hypothesized that cyclooxygenase-2 (COX2) would affect remodelling in 12-month-old obese rats compared with young rats. METHODS AND RESULTS: Mesenteric arteries of obese and lean Zucker rats were alternatively ligated to generate high flow (HF) in the median artery. After 21 days, arteries were isolated for in vitro analysis. After 21 days, outward hypertrophic remodelling occurred in HF arteries in obese (498 +/- 20 vs. 443 +/- 18 mum intraluminal diameter in normal flow (NF) arteries, P < 0.01), but not in lean rats (454 +/- 17 vs. 432 +/- 14, NS; n = 12 per group). Endothelium-dependent (acetylcholine)-mediated relaxation (AMR) was lower in obese than in lean rats. AMR was reduced by NO-synthase blockade in all groups, and eNOS expression was higher in HF than in NF arteries without difference between lean and obese rats. Indomethacin further reduced AMR in HF arteries from obese rats only. Obesity increased COX2 immunostaining in mesenteric arteries. Acute COX2 inhibition (NS398) significantly reduced AMR in HF arteries from obese rats only, suggesting production of vasodilator prostanoid(s). In obese rats chronically treated with the COX2 inhibitor celecoxib, outward remodelling did not occur in HF arteries and AMR was improved without reaching the level found in lean rats. CONCLUSION: COX2 preserved in part flow-mediated arterial remodelling in old obese rats. Nevertheless, this effect was not sufficient to keep endothelium-dependent relaxation to the level obtained in lean rats

Dose effect activity of ferrocifen-loaded lipid nanocapsules on a 9L-glioma model

Ferrociphenol (Fc-diOH) is a new molecule belonging to the fast-growing family of organometallic anti-cancer drugs. In a previous study, we showed promising in vivo results obtained after the intratumoural subcutaneous administration of the new drug-carrier system Fc-diOH-LNCs on a 9L-glioma model. To further increase the dose of this lipophilic entity, we have created a series of prodrugs of Fc-diOH. The phenol groups were protected by either an acetyl (Fc-diAc) or by the long fatty-acid chain of a palmitate (Fc-diPal). LNCs loaded with Fc-diOH prodrugs have to be activated in situ by enzymatic hydrolysis. We show here that the protection of diphenol groups with palmitoyl results in the loss of Fc-diOH in vitro activity, probably due to a lack of in situ hydrolysis. On the contrary, protection with an acetate group does not affect the strong, in vitro, antiproliferative effect of ferrocifen-loaded-LNCs neither the reduction of tumour volume observed on an ectopic model, confirming that acetate is easily cleaved by cell hydrolases. Moreover, the cytostatic activity of Fc-diOH-LNCs is confirmed on an orthotopic glioma model since the difference in survival time between the infusion of 0.36 mg/rat Fc-diOH-LNCs and blank LNCs is statistically significant. By using LNCs or Labrafac to carry the drug, a dose-effect ranging from 0.005 to 2.5mg of Fc-diOH per animal can be evidenced

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-beta-estradiol (E2) has a key role in this process through activation of estrogen receptor alpha (ERalpha). Thus, we investigated the impact of age and timing for estrogen efficacy on FMR. APPROACH AND 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, ERalpha and endothelial nitric oxide synthase expression were reduced by half compared with age-matched rats recently ovariectomized. FMR did not occur in ERalpha(-/-) mice, whereas it was decreased by 50% in ERalpha(+/-) 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