H aploinsufficiency of elastin in patients with WilliamsBeuren syndrome leads, in more than half of cases, to development of supravalvular aortic stenosis and hypertension.1 Moreover, Eln +/− mice, a model for supravalvular aortic stenosis disease, have a higher arterial pressure (∆25-30 mm Hg) than their wild-type counterparts.2 These cardiovascular features are clearly linked to the decreased elastin synthesis in the aorta during development. Thus, it would be of interest to find molecules able to enhance elastin synthesis to treat this condition.We previously showed that the Brown Norway (BN) rat, a normotensive inbred strain, presents the lowest content of elastin in the aorta compared with 6 other inbred rat strains. [3][4][5] We also demonstrated that, compared with the LOU rat, the elastin deficit in the thoracic aorta of the BN rat is partly caused by a decrease in the synthesis of tropoelastin (TE), the soluble precursor of elastin. However, elastin gene polymorphism accounts for only 3.9% of the elastin content variance in F2 BNxLOU rats.4 After a genome-wide search for quantitative trait loci influencing the aortic elastin content in an F2 population derived from BN and LOU rats, we identified on chromosomes 2 and 14, 3 quantitative trait loci specifically controlling elastin levels: Ael1, Ael2, and Ael3. 6 The polymorphic marker, D2Wox26, corresponding to the maximum logarithm of odds score value of Ael2, is situated within the gene encoding for the Na + /K + -ATPase α1 subunit. In addition, several other genes encoding for potassium channels are contained in Ael1 (Kcnmb2, Hcn1) and Ael2 (Hcn3, Kcnn3, Kcnd3, Kcna2, Kcna3, and Kcna10). This result supports the hypothesis that the deficit of aortic elastin content in the BN rat could be explained by anomalies in intracellular potassium concentration ([K + ] i ).Abstract-Hypertension is a cardiovascular disorder that appears in more than half of the patients with Williams-Beuren syndrome, hemizygous for the elastin gene among 26 to 28 other genes. It was shown that the antihypertensive drug minoxidil, an ATP-dependent potassium channel opener, enhances elastic fiber formation; however, no wide clinical application was developed because of its adverse side effects. The Brown Norway rat was used here as an arterial elastin-deficient model. We tested 3 different potassium channel openers, minoxidil, diazoxide, and pinacidil, and 1 potassium channel blocker, glibenclamide, on cultured smooth muscle cells from Brown Norway rat aorta. All tested potassium channel openers increased mRNAs encoding proteins and enzymes involved in elastic fiber formation, whereas glibenclamide had the opposite effect. The higher steady-state level of tropoelastin mRNA in minoxidil-treated cells was attributable to an increase in both transcription and mRNA stability. Treatment of Brown Norway rats for 10 weeks with minoxidil or diazoxide increased elastic fiber content and decreased cell number in the aortic media, without changing collagen content. The minoxidil-induced card...

To analyze age-related interactions between obesity, its associated metabolic disorders, and macrocirculation, we studied large artery stiffness and fatty acid responsiveness in lean and obese Zucker rats, aged 25 (adult) and 80 weeks (very old). Systolic arterial pressure was higher in old obese than in old lean rats (178 ± 10 vs 134 ± 8 mmHg, respectively). Carotid elastic modulus-wall stress curves showed increased age-dependent arterial stiffening, which was greater in obese animals. Old obese exhibited endothelial dysfunction with increased systemic oxidative stress. Adult obese had elevated plasma free fatty acid levels (1,866 ± 177 vs 310 ± 34 μg/μL in lean animals). In old obese, linoleate and palmitate increased contractility to phenylephrine and reduced relaxation to acetylcholine. Thus, obesity at 25 weeks appears to trigger accelerated arterial aging observed at 80 weeks. The early increase in free fatty acids may be a key effector in the severe arterial stiffness of the aged obese Zucker model.