Bisphenol A (BPA) is found in human urine and fat tissue. Higher urinary BPA concentrations are associated with arterial hypertension. To shed light on the underlying mechanism, we orally administered BPA (4 nM to 400 μM in drinking water) to 8-wk-old CD11 mice over 30 d. Mice developed dosage-dependent high blood pressure (systolic 130 ± 12 vs. 170 ± 12 mmHg; EC50 0.4 μM), impairment of acetylcholine (AcH)-induced carotid relaxation (0.66 ± 0.08 vs. 0.44 ± 0.1 mm), a 1.7-fold increase in arterial angiotensin II (AngII), an 8.7-fold increase in eNOS mRNA and protein, and significant eNOS-dependent superoxide and peroxynitrite accumulation. AngII inhibition with 0.5 mg/ml losartan reduced oxidative stress and normalized blood pressure and endothelium-dependent relaxation, which suggests that AngII uncouples eNOS and contributes to the BPA-induced endothelial dysfunction by promoting oxidative and nitrosative stress. Microarray analysis of mouse aortic endothelial cells revealed a 2.5-fold increase in expression of calcium/calmodulin-dependent protein kinase II-α (CaMKII-α) in response to 10 nM BPA, with increased expression of phosphorylated-CaMKII-α in carotid rings of BPA-exposed mice, whereas CaMKII-α inhibition with 100 nM autocamptide-2-related inhibitor peptide (AIP) reduced BPA-mediated increase of superoxide. Administration of CaMKII-α inhibitor KN 93 reduced BPA-induced blood pressure and carotid blood velocity in mice, and reverted BPA-mediated carotid constriction in response to treatment with AcH. Given that CaMKII-α inhibition prevents BPA-mediated high blood pressure, our data suggest that BPA regulates blood pressure by inducing AngII/CaMKII-α uncoupling of eNOS.

Results: ILK expression was detected in the endothelial cell layer of nonatherosclerotic vessels but was absent from the endothelium of atherosclerotic arteries. Live ultrasound imaging revealed that acetylcholine-mediated vasodilatation was impaired in cKO mice. These mice exhibited lowered agonist-induced nitric oxide synthase (NOS) activity and decreased cyclic guanosine monophosphate and nitrite production. ILK deletion caused endothelial NOS (eNOS) uncoupling, reflected in reduced tetrahydrobiopterin (BH4) levels, increased BH2 levels, decreased dihydrofolate reductase expression, and increased eNOS-dependent generation of superoxide accompanied by extensive vascular protein nitration. ILK reexpression prevented eNOS uncoupling in cKO cells, whereas superoxide formation was unaffected by ILK depletion in eNOS-KO cells, indicating eNOS as a primary source of superoxide anion. eNOS and ILK coimmunoprecipitated in aortic lysates from control animals, and eNOS-ILK-shock protein 90 interaction was detected in human normal mammary arteries but was absent from human atherosclerotic carotid arteries. eNOS-ILK interaction in endothelial cells was prevented by geldanamycin, suggesting heat shock protein 90 as a binding partner. Key Words: atherosclerosis Ⅲ oxidative stress Ⅲ uncoupling protein E ndothelial dysfunction is defined as impaired endothelium-dependent relaxation of blood vessels in response to the endogenous vasodilator nitric oxide (NO). Endothelial dysfunction is concomitant with changes in vascular structure associated with many forms of vascular disease, such as hypertension and atherosclerosis. 1 Atherosclerotic lesions develop mostly in areas exposed to disturbed blood flow, whereas endothelial cells exposed to laminar flow are protected against inflammatory activation and show higher relative expression of endothelial NO synthase (eNOS) and superoxide dismutase. 2,3 Most NO in the vasculature is produced by eNOS, with a minor contribution from neuronal-type nNOS expressed in vascular smooth muscle cells. Under inflammatory conditions, vascular cells can express iNOS, which produces large amounts of NO and contributes further to vascular damage. 4 eNOS can be activated by hemodynamic forces, autacoids, hormones, and growth factors. NO relaxes vessels via activation of soluble guanylyl cyclase (sGC). The resulting elevated levels of cyclic guanosine monophosphate (cGMP) activate cGMP-dependent protein kinase type I (cGKI), which phosphorylates downstream targets that regulate the Original received July 29, 2011; revision received December 13, 2011; accepted December 14, 2011. In November 2011 actin-myosin cytoskeleton and the calcium clearing mechanism, leading to vasorelaxation. 5 Many endothelial cell molecules, including integrins, sense shear stress. 6,7 Integrin-linked kinase (ILK), a key regulator of blood vessel integrity, is a phosphoinositide 3-kinasedependent serine/threonine kinase that binds to the cytoplasmic domain of ß-integrin and lies upstream of many intracellular signaling pa...

The discovery of a connection between endothelial cell structures such as cilia, integrin, extracellular matrix, and signaling events opens today a new chapter in our understanding of the molecular mechanisms regulating vascular responses to the changes in flow.

The current study consisted of four experiments that utilised a novel approach to investigating false memories. Each of the experiments in the current study investigated individuals with varying experience with different languages. Experiment 1 tested participants in both their native and secondary languages as well as monolingual English speakers, while Experiment 2 assessed native Spanish speakers using both English and Spanish associative lists. Experiment 3 examined the illusory memories in monolingual Spanish speakers in both English and Spanish, while Experiment 4 investigated false memories in monolingual English speakers in both English and Spanish. Results indicated that memory for list items and critical lures was greatest when the lists were presented in the participants' primary language. Results can be explained by either activation-based or fuzzy-trace theories.