Abstract-Both known estrogen receptors, ER␣ and ER␤, are expressed in blood vessels. To gain further insight into the role of ER␣ in a functional setting, we investigated the effect of the novel highly selective ER␣ agonist Cpd1471 on vascular reactivity in ovariectomized spontaneously hypertensive rats (SHR). After ovariectomy or sham operation, 12-week-old female SHR received either 17␤-estradiol (E2, 2 g/kg body wt per day), the selective ER␣ agonist Cpd1471 (30 g/kg body wt per day), or placebo. Acetylcholine-induced endothelium-dependent vasorelaxation was significantly blunted in aortas from ovariectomized rats (R max , 53%Ϯ3% versus sham, 79%Ϯ2%; PϽ0.001). Treatment with E2 or Cpd1471 significantly augmented acetylcholine-induced relaxation in ovariectomized rats (R max , 70%Ϯ2%; resp, 73%Ϯ2%). Endothelium-independent relaxation induced by sodium nitroprusside was not different among the four groups. The contractile response induced by the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine, an index of basal NO formation, was significantly lower in ovariectomized rats compared with sham-operated animals (53Ϯ2% versus 77%Ϯ5%; PϽ0.01) and was normalized by both E2 (70%Ϯ2%) and Cpd1471 (70%Ϯ3%). Aortic endothelial NO synthase (eNOS) expression and phosphorylation of the vasodilator-stimulated phosphoprotein, an index of NO/cGMP-signaling, was reduced in ovariectomized SHR and normalized by E2 and Cpd1471. In SHR after ovariectomy, endothelium-dependent NO-mediated vasorelaxation and eNOS expression are attenuated. The novel selective ER␣ agonist Cpd1471 prevented these pathophysiological changes to a similar extent as E2. Thus, the pharmacological principle of selective ER␣ activation mediates positive vascular effects. Key Words: estrogen Ⅲ endothelium Ⅲ nitric oxide Ⅲ nitric oxide synthase Ⅲ rats, spontaneously hypertensive G ender differences in the risk for cardiovascular diseases are well recognized, with premenopausal women exhibiting a lower risk than age-matched men. The advantage of women over men in cardiovascular morbidity disappears after menopause, suggesting that estrogen plays an important role in cardiovascular health. 1 Estrogens are known to exert beneficial effects on the vascular wall. Long-term estrogen treatment improves endothelial dysfunction, a major contributor to the pathophysiology of cardiovascular disease, through upregulation of endothelial cell genes, such as endothelial nitric oxide synthase (eNOS). 2-4 Furthermore, estrogen has rapid nongenomic effects on the vascular endothelium, including activation of nitric oxide (NO) synthesis. 5,6 However, despite the positive effects on vascular function in animal models 7-9 and humans, 10 -14 estrogen replacement therapy with 17␤-estradiol or mixtures of equine estrogens as in the Heart and Estrogen/progestin Replacement Study (HERS) has failed to protect from cardiovascular diseases in large controlled clinical trials. [15][16][17][18] Therefore, in recent years, research has focused on selective estrogen receptor modulation as...

Ligand-dependent activation of ERbeta confers blood pressure lowering effects in SHR that are superior to those of 17beta-estradiol or the ERalpha agonist 16alpha-LE2 and attenuates cardiac hypertrophy primarily by a reduction of cardiac afterload without promoting uterine growth.

Acquired forms of prion diseases or transmissible spongiform encephalopathies are believed to occur following peripheral exposure. Prions initially accumulate in the lymphoid system before spreading to the nervous system, but the underlying mechanisms for prion transfer between the two systems are still elusive. Here we show that ablation of the B-cell-specific transmembrane protein CD19, a coreceptor of the complement system, results in an acceleration of prion neuroinvasion. This appears to be due to an alteration of the follicular dendritic cell (FDC) network within the lymphoid tissue, thereby reducing the distance between FDCs and adjacent nerve fibers that mediate prion neuroinvasion.