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  • d'Uscio, Livius V  (9)
  • 1
    Online Resource
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    Abstract P274: Endothelial Dysfunction of Conduit Arteries in Amyloid Precursor Protein-Deficient Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Hypertension Vol. 72, No. Suppl_1 ( 2018-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 72, No. Suppl_1 ( 2018-09)
    Abstract: Amyloid precursor protein (APP) is an integral membrane protein expressed in the peripheral arteries. However, the exact vascular physiological function of APP is unknown. Male APP-deficient (APP –/– ) and their wild-type littermates (WT) mice were used to characterize the phenotype of APP in the control of vascular function. Isometric force of isolated aortic rings was recorded in organ chambers. Circulating levels of norepinephrine and epinephrine were significantly enhanced in APP –/– mice (4723±566 pg/mL and 854±98 pg/mL, respectively P 〈 0.05 vs. WT: 1999±319 pg/mL and 429±71 pg/mL, respectively; n=13). The efficacy of phenylephrine induced contractions were significantly reduced in the aorta of APP –/– mice (21±3%, P 〈 0.05 vs. WT: 47±4%; n=10) while contractions to prostaglandin F 2α were unchanged (135±4%, P=n.s. vs. WT: 133±3%; n=9). Western blot analysis revealed that protein expression of alpha1D adrenergic receptors was significantly downregulated in APP –/– mice aortas (0.21±0.05 O.D.; P 〈 0.05 vs. WT: 0.48±0.11 O.D.; n=6). In contrast, endothelium-dependent relaxations to β-agonist isoproterenol were significantly enhanced in APP –/– mice aortas (P 〈 0.05; n=10) while endothelium-dependent relaxations to acetylcholine were unaltered (P=n.s.; n=12). Incubation of aortic rings with indomethacin significantly impaired relaxations to isoproterenol as well as acetylcholine in APP –/– mice (P 〈 0.05; n=8) while concomitant treatment with NOS inhibitor L-NAME completely abolished relaxations to both agonists (P 〈 0.05; n=6-7). Incubation of aortic rings with isoproterenol significantly increased cAMP in the aortas of APP –/– mice (16.2±4.1 pmol/mg; P 〈 0.05 vs. WT: 6.6±4.1 pmol/mg; n=7). Furthermore, cAMP levels were significantly enhanced by acetylcholine in APP –/– mice aortas (38±9 pmol/mg; P 〈 0.05 vs. WT: 14±3 pmol/mg; n=8) while acetylcholine stimulated cGMP levels were reduced (59±5 pmol/mg; P 〈 0.05 vs. WT: 83±7 pmol/mg; n=12). Our results suggest that increased circulating levels of catecholamines in APP –/– mice are responsible for observed vascular phenotype. These findings indicate that under physiological conditions, APP expression plays an important role in control of vascular endothelial function .
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.72.suppl_1.P274
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2094210-2
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  • 2
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    Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels
    SAGE Publications ; 2017
    In:  Journal of Cerebral Blood Flow & Metabolism Vol. 37, No. 1 ( 2017-01), p. 106-122
    Details
    In: Journal of Cerebral Blood Flow & Metabolism, SAGE Publications, Vol. 37, No. 1 ( 2017-01), p. 106-122
    Abstract: We tested hypothesis that activation of the prostacyclin (PGI 2 ) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI 2 , iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuroprotective and anticoagulant molecule, soluble APPα (sAPPα). Selective agonist of IP receptor, cicaprost, and adenylyl cyclase activator, forskolin, also enhanced expression of amyloid precursor protein and ADAM10. Notably, in cerebral microvessels of IP receptor knockout mice, protein levels of APP and ADAM10 were reduced. In addition, iloprost increased protein levels of peroxisome proliferator-activated receptor δ (PPARδ) in human brain microvascular endothelial cells. PPARδ-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPARδ) upregulated ADAM10 and increased production of sAPPα. Genetic deletion of endothelial PPARδ (ePPARδ −/− ) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPPα. In vivo treatment with GW501516 increased sAPPα content in hippocampus of wild type mice but not in hippocampus of ePPARδ −/− mice. Our findings identified previously unrecognized role of IP-PPARδ signal transduction pathway in the production of sAPPα in cerebral microvasculature.
    Type of Medium: Online Resource
    ISSN: 0271-678X , 1559-7016
    URL: Article
    DOI: 10.1177/0271678X15618977
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2017
    detail.hit.zdb_id: 2039456-1
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  • 3
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    Impairment of amyloid precursor protein alpha-processing in cerebral microvessels of type 1 diabetic mice
    SAGE Publications ; 2019
    In:  Journal of Cerebral Blood Flow & Metabolism Vol. 39, No. 6 ( 2019-06), p. 1085-1098
    Details
    In: Journal of Cerebral Blood Flow & Metabolism, SAGE Publications, Vol. 39, No. 6 ( 2019-06), p. 1085-1098
    Abstract: The mechanisms underlying dysfunction of cerebral microvasculature induced by type 1 diabetes (T1D) are not fully understood. We hypothesized that in cerebral microvascular endothelium, α-processing of amyloid precursor protein (APP) is impaired by T1D. In cerebral microvessels derived from streptozotocin (STZ)-induced T1D mice protein levels of APP and its α-processing enzyme, a disintegrin and metalloprotease 10 (ADAM10) were significantly decreased, along with down-regulation of adenylate cyclase 3 (AC3) and enhanced production of thromboxane A 2 (TXA 2 ). In vitro studies in human brain microvascular endothelial cells (BMECs) revealed that knockdown of AC3 significantly suppressed ADAM10 protein levels, and that activation of TXA 2 receptor decreased APP expression. Furthermore, levels of soluble APPα (sAPPα, a product of α-processing of APP) were significantly reduced in hippocampus of T1D mice. In contrast, amyloidogenic processing of APP was not affected by T1D in both cerebral microvessels and hippocampus. Most notably, studies in endothelial specific APP knockout mice established that genetic inactivation of APP in endothelium was sufficient to significantly reduce sAPPα levels in the hippocampus. In aggregate, our findings suggest that T1D impairs non-amyloidogenic processing of APP in cerebral microvessels. This may exert detrimental effect on local concentration of neuroprotective molecule, sAPPα, in the hippocampus.
    Type of Medium: Online Resource
    ISSN: 0271-678X , 1559-7016
    URL: Article
    DOI: 10.1177/0271678X17746981
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2019
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  • 4
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    Abstract W P230: Tetrahydrobiopterin Attenuates Cerebrovascular Oxidative Stress in Tg2576 Mouse Model of Alzheimer’s Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Stroke Vol. 46, No. suppl_1 ( 2015-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 46, No. suppl_1 ( 2015-02)
    Abstract: Background: The present study was designed to test the hypothesis that supplementation of tetrahydrobiopterin (BH4) to transgenic mice expressing the Swedish double mutation of human amyloid precursor protein (Tg2576 mice) results in restoration of BH4 levels required for activation of endothelial nitric oxide synthase (eNOS), and in turn, prevents oxidative stress in cerebral microvasculature. Methods: Cerebral microvessels were obtained from 4-5 months old female wild-type and Tg2576 mice. Biopterin levels, enzymatic activity of GTP cyclohydrolase I (GTPCH-I) and superoxide production were measured by HPLC. The effects of supplementation of BH4 on oxidative stress were studied by injecting wild-type and Tg2576 mice subcutaneously with 100 mol/kg (b.w.) of BH 4 ([ 6R ]-5,6,7,8-tetrahydro-L-biopterin dihydrochloride; [ 6R ]-BH4). Results: Enzymatic activity of GTPCH-I, rate limiting enzyme in BH4 biosynthesis, was not different between cerebral microvessels of wild-type and Tg2576 mice. However, bioavailability of BH4, was significantly reduced in cerebral microvessels of Tg2576 mice (P 〈 0.05, n=8). Production of superoxide anions was significantly elevated in cerebral microvessels of Tg2576 mice (P 〈 0.01, n=6), indicative of oxidative stress. This increased superoxide anion production was abolished by L-NAME, a NOS inhibitor, suggestive of eNOS uncoupling (P 〈 0.05, n=6). Supplementation of [ 6R ]-BH4 to wild-type and Tg2576 mice resulted in significant increase in BH4 bioavailability (P 〈 0.05, n=6). Notably, supplementation of [ 6R ]-BH4 abrogated the increase in superoxide anion production in cerebral microvessels of Tg2576 mice (P 〈 0.05, n=5), while superoxide anion production remained unchanged in cerebral microvessels of WT mice. Furthermore, the inhibitory effects of L-NAME on superoxide anion production in cerebral microvessels of Tg2576 mice were abolished following [ 6R ]-BH4 supplementation (P 〈 0.05, n=4). Conclusion: Supplementation of [ 6R ]-BH4 restored bioavailability of BH4, thereby abrogating superoxide anion production derived from eNOS. Our results suggest that uncoupling of eNOS contributes to oxidative stress in cerebral microvessels of Tg2576 mice.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.46.suppl_1.wp230
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1467823-8
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  • 5
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    Reduced bioavailability of tetrahydrobiopterin impairs neovascularization after hind limb ischemia
    Wiley ; 2010
    In:  The FASEB Journal Vol. 24, No. S1 ( 2010-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 24, No. S1 ( 2010-04)
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v24.S1
    DOI: 10.1096/fasebj.24.1_supplement.754.3
    Language: English
    Publisher: Wiley
    Publication Date: 2010
    detail.hit.zdb_id: 1468876-1
    SSG: 12
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  • 6
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    Abstract 25: Peroxisome Proliferator Activated Receptor - δ Agonist GW501516 Restores Bioavailability Of Tetrahydrobiopterin And Prevents Cerebral Vascular Dysfunction In Tg2576 Mice Overexpressing Amyloid Precursor Protein
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Stroke Vol. 43, No. suppl_1 ( 2012-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. suppl_1 ( 2012-02)
    Abstract: Objectives- Oxidative stress and endothelial dysfunction precedes cerebral β-amyloid deposits in human Alzheimer’s disease as well as in transgenic mouse models expressing mutations in amyloid precursor protein (APP). In the present study, we hypothesized that uncoupling of endothelial nitric oxide synthase (eNOS) caused by loss of its essential co-factor, tetrahydrobiopterin (BH 4 ), in cerebral arteries and microvessels contributes, in part, to oxidative stress and cerebral vascular dysfunction in a APP transgenic mouse (Tg2576) that express the Swedish double mutation of human APP. In addition, we examined whether treatment with Peroxisome Proliferator Activated Receptor-δ (PPARδ) activator - GW501516 restores bioavailability of BH 4 and reverses oxidative stress in APP Tg2576 mice. Methods- APP Tg2576 mice (4-5 months old) were treated with GW501516 , a selective PPARδ activator (2 mg/kg/day, po, 14 days). Following treatment, cerebral arteries and microvessels were obtained. Biopterin levels, enzymatic activity of GTP cyclohydrolase I (GTPCH I) and superoxide production were measured by HPLC and protein expression was studied by Western blotting. Results- Cerebral arteries and microvessels demonstrated increased expression of eNOS, while the bioavailability of its essential co-factor BH 4 was significantly reduced, suggestive of eNOS uncoupling in APP Tg2576 mice. Furthermore, expressions of catalase and manganese superoxide dismutase (MnSOD) were decreased, while superoxide production was increased (P 〈 0.01, n=6) in cerebral microvessels of APP Tg2576 mice. Treatment with GW501516 restored the BH 4 /BH 2 ratio in cerebral arteries and microvessels of APP Tg2576 mice (P 〈 0.05, n-7-8), while the enzymatic activity of GTPCH-I remained unchanged (P 〉 0.05, n=6). PPARδ activation also prevented the attenuation in expressions of MnSOD and catalase, and inhibited the increased superoxide production (P 〈 0.05, n=6) in cerebral arteries and microvessels of APP Tg2576 mice. Interestingly, PPARδ activation significantly inhibited the over-expression of APP in cerebral microvessels obtained from APP Tg2576 mice (P 〈 0.001, n=4). Conclusion- Our results suggest that endothelial dysfunction in APP Tg2576 mice may be caused, in part, by reduced bioavailability of BH 4 and uncoupling of eNOS. Treatment of APP Tg2576 mice with PPARδ agonist GW501516 exerted cerebral vascular protection by multiple mechanisms: (a) by inhibiting eNOS uncoupling via increased expressions of MnSOD and catalase, as well as, (b) by attenuating the increased expression of APP in the cerebral microvessels of APP Tg2576 mice.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.43.suppl_1.A25
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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  • 7
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    Abstract 130: Effects of Genetic Inactivation of Amyloid Precursor Protein in Cerebral Microvasculature
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Stroke Vol. 45, No. suppl_1 ( 2014-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. suppl_1 ( 2014-02)
    Abstract: Background: Amyloid precursor protein (APP) is expressed in neuronal and non-neuronal tissues in the brain, including cerebrovascular endothelium. However, the physiological role of APP in cerebral vasculature is not completely understood. The present study was designed to determine the effects of inactivation of APP in cerebral microvasculature. Methods: Effect of genetic inactivation of APP was studied both in vitro and in vivo . Cultured human brain microvascular endothelial cells (hBMECs) were incubated with APP-siRNA in vitro , while control-siRNA treated hBMECs served as controls. To study the effect of genetic inactivation of APP in vivo , cerebral microvessels were obtained from APP-deficient (APPKO) mice. Cerebral microvessels from wild-type (C57BL/6) littermates served as controls. Results: Silencing APP expression in hBMECs resulted in selective reduction in endothelial nitric oxide synthase (eNOS) expression (P 〈 0.05, n=6), while expressions of inducible NOS and prostacyclin (PGI2) synthase remained unchanged. Furthermore, loss of APP in hBMECs resulted in significantly increased production (P 〈 0.05, n=5) of superoxide anions, as determined by quantitation of 2-hydroxyethidium from dihydroethidium using HPLC. In line with the results obtained from in vitro studies, cerebral microvessels of APPKO mice also demonstrated increased production of superoxide anions. Furthermore, levels of cGMP, second messenger of endothelial NO, were significantly attenuated in cerebral microvessels of APPKO mice, while levels of cAMP remained unchanged. Conclusions: Our results suggest that genetic inactivation of APP results in oxidative stress and impairment of endothelial NO signaling. We speculate that APP exerts vascular protective effects in the cerebral circulation under physiological conditions.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.45.suppl_1.130
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 8
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    Abstract T P246: Phenotypic Characterization of Cerebral Microvasculature in Transgenic Mice With Endothelium Targeted Over-expression of GTP Cyclohydrolase I
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Stroke Vol. 46, No. suppl_1 ( 2015-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 46, No. suppl_1 ( 2015-02)
    Abstract: Background: Optimal availability of tetrahydrobiopterin (BH4) is a critical determinant of nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) in the vascular endothelium. Biosynthesis of BH4 is regulated by the enzymatic activation of GTP cyclohydrolase I (GTPCH-I). While the physiological role of GTPCH-I and BH4 have been extensively characterized in peripheral vasculature, their role in regulation of cerebral vascular function has not been investigated. Methods: The role of GTPCH-I in regulation of cerebral vascular function was studied in cerebral microvessels isolated from wild-type (WT) mice and from mice with endothelium-targeted overexpression of GTPCH-I (eGTPCH-I Tg) mice. Vascular protein expression, intracellular levels of biopterin and cGMP (second messenger of NO) as well as production of NO and superoxide anions were determined. Results: Endothelium targeted over-expression of GTPCH-I resulted in significant increase in levels of BH4, as well as its oxidized product, 7,8-dihydrobiopterin (7,8-BH2). Importantly, ratio of BH4 to 7,8-BH2, indicative of BH4 available for eNOS activation, was significantly increased in cerebral microvessels of eGTPCH-I Tg mice. However, protein expression of eNOS, levels of nitrate/nitrite - indicative of NO production remained unchanged between cerebral microvessels of WT mice and eGTPCH-I Tg mice. Furthermore, increased BH4 biosynthesis did not affect production of superoxide anions or expression of antioxidant enzymes. Moreover, intracellular levels of cGMP, reflective of NO signaling and activation of soluble guanylate cyclase, were not affected in eGTPCH-I Tg mice. Conclusion: Our results suggest that, despite a significant increase in BH4 bioavailability, generation of endothelial NO in cerebral microvessels remained unchanged in eGTPCH-I Tg mice. We conclude that under physiological conditions the levels of BH4 are optimal for activation of eNOS and NO/cGMP signaling in wild-type mice.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.46.suppl_1.tp246
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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  • 9
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    Abstract W MP84: Erythropoietin Inhibits Oxidation of Tetrahydrobiopterin and Restores Bioavailability of Endothelial Nitric Oxide in Cerebral Microvessels of Hph-1 Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Stroke Vol. 45, No. suppl_1 ( 2014-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. suppl_1 ( 2014-02)
    Abstract: Background: While reported neuroprotective effects of erythropoietin (EPO) make it an appealing candidate for its evaluation in protection of neurovascular unit during cerebrovascular or neurodegenerative disorders, effects of EPO on cerebral microvessels, the vascular component of neurovascular unit, have not been studied to date. The present study was designed to determine the effects of EPO in cerebral microvessels derived from wild-type mice and also from hph-1 mice, a genetic mouse model of BH4 deficiency. Methods: Hph-1 mice and wild-type littermates (C57BL/6 background) were administered recombinant human EPO (1000 U/kg/day) intraperitoneally for 3 days. Following treatment, mice were killed by injection of an overdose of pentobarbital, brains were removed and cerebral microvessels were isolated. Results: Treatment of wild-type mice with EPO did not affect BH4 bioavailability, superoxide anion production or basal cGMP levels. We have reported that cerebral microvessels of hph-1 mice demonstrated reduced bioavailability of BH4, increased production of superoxide anions and impaired endothelial NO/cGMP signaling. Treatment of hph-1 mice with EPO attenuated the levels of 7,8-dihydrobiopterin (7,8-BH2; P 〈 0.05, n=5), oxidized product of BH4, and significantly increased the ratio of BH4 to 7,8-BH2 (P 〈 0.05, n=5), indicative of increased bioavailability of BH4 for eNOS activation. Increased superoxide anion production in cerebral microvessels of hph-1 mice were attenuated by EPO treatment (P 〈 0.05, n=5). While eNOS expression remained unchanged, levels of cGMP were significantly increased on EPO treatment in hph-1 mice (P 〈 0.05, n=6). Furthermore, EPO treatment selectively increased expression of manganese superoxide dismutase. Conclusion: The ability of EPO to attenuate oxidative stress and restore bioavailability of endothelial NO in cerebral microvessels may help to explain mechanisms responsible for cerebrovascular protective effects of EPO.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.45.suppl_1.wmp84
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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