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  • In view of the hypotensive effect


    In view of the hypotensive effect of endothelial-specific overexpression of eNOS [17], [19], [28] we correlated skeletal muscle eNOS expression with sBP including data on colony 5 of eNOS-Tg [17] which was used to generate eNOS-Tg/KO (Fig. 4D). We found a highly significant one phase exponential decay (R2 =0.992) described by the equation Y=SPAN·e(−K·X) + Plateau (Y=sBP; SPAN=35.56; X=Expression; K=0.00720; Plateau=102.3) and similar values were found for the correlation of aortic eNOS expression and sBP (R2 =0.9992; SPAN=35.92; K=0.00727; Plateau=102.0). Using these equations the expected sBP calculated for eNOS-Tg/KO was 126.0 and 124.5 mmHg, respectively. Hence, the predicted reduction of ≥12 mmHg of sBP in eNOS-Tg/KO did not occur. Moreover, we observed not even a part of this expected reduction of sBP regardless of the method of measurement suggesting that endothelial-specific and thus vascular expression of eNOS alone appears not sufficient to reduce BP cam kinase ii in eNOS-KO. It has been shown that both expression and activity of vascular extracellular SOD (ecSOD) are dependent on bioavailability of vascular endogenous NO and are largely reduced in eNOS-KO [24], [29]. Likewise, upregulation of eNOS by exercise triggers induction of ecSOD expression [24]. In striking contrast to lower expression levels of ecSOD in eNOS-KO, the expression of ecSOD in eNOS-Tg/KO was elevated to the levels observed in cam kinase ii and in skeletal muscle of C57BL/6. We observed also no difference in the expression of other important proteins which may modify and/or compensate for the activity of vascular NO. For example, there was no change in the expression of the NO receptor sGCβ1- and α1-subunits which confirms previous results on sGC expression and activity in eNOS-KO [6] as well as eNOS-Tg [17]. Despite the small amount of nNOS present in blood vessel nerves, it has been reported that low levels of nNOS-derived NO could compensate for the lack of eNOS when eNOS activity is compromised. For instance, nNOS-cGMP-dependent pathways dilated pial arterioles [14] and nNOS–derived NO contributed to the flow-induced responses in coronary arteries of eNOS-KO [30]. However, there was no compensatory upregulation of nNOS protein in aortic and skeletal muscles of eNOS-Tg/KO as compared to C57BL/6 suggesting that such effects unlikely contributed in eNOS-Tg/KO to the effects of acetylcholine and l-NAME in aortic rings and in vivo. Finally, we investigated whether eNOS-Tg/KO show an increase of protein tyrosine nitration which likely reduces vascular NO-bioavailability [31] and found no differences between the strains. Thus, examination of the expression levels of important proteins associated with vascular NO-activity showed no alterations which would call into question a normal vascular NO activity. Taken together our data demonstrate a previously unrecognized obligatory role of extra-endothelial eNOS in the physiologic regulation of BP. They open the perspective that non-endothelial eNOS impairment may contribute to the pathogenesis of hypertension which is complex, multifactorial and incompletely understood [32]. Several extra-endothelial locations of eNOS might be of particular importance [33], [34], [35]. For example, there is considerable evidence that NO in the central nervous system affects sympathetic nerve activity and modulates BP and heart rate [36], [37]. Our novel mouse model might also be a useful tool to study whether current antihypertensive treatments are similarly effective if non-endothelial eNOS is missing.
    Conflict of interest
    Acknowledgments This study was supported by research Grant of DFG (SU 783/1-1 to T.S.) and Forschungs-kommission of the Heinrich-Heine-University Düsseldorf (Project 9772 446 to T.S.).
    Introduction Psoriasis is a hyper proliferative, immunologically mediated chronic inflammatory skin disease which is characterized by erythematous scaly skin plaques (Gudjonsson and Elder, 2007). It affects about 2–4% population globally, according to different studies the prevalence of psoriasis varies according to the demographic characteristics of certain populations (Lima et al., 2013, Parisi et al., 2013). The molecular basis of psoriasis is poorly understood, yet genetics and environment both are believed to play somewhat equal role in susceptibility and severity of the disease (Ogretmen et al., 2014).