TY - JOUR
T1 - Characterization of cerebral microvasculature in transgenic mice with endothelium targeted over-expression of GTP-cyclohydrolase i
AU - Santhanam, Anantha Vijay R.
AU - D'Uscio, Livius V.
AU - Katusic, Zvonimir S.
N1 - Funding Information:
No conflicts of interest, financial or otherwise, are declared by the author(s). This study was funded in part by National Institutes of Health, United States Grant ( HL111062 ) to ZSK, Mayo Clinic Alzheimer׳s Disease Research Center Pilot Grant (to AVS), and the Mayo Foundation .
Publisher Copyright:
© 2015 Elsevier B.V.
PY - 2015/11/2
Y1 - 2015/11/2
N2 - Tetrahydrobiopterin (BH4) is a critical determinant of nitric oxide (NO) production by nitric oxide synthase (NOS) in the vascular endothelium and its biosynthesis is regulated by the enzymatic activity of GTP-cyclohydrolase I (GTPCH I). The present study was designed to determine the effects of endothelium-targeted overexpression of GTPCH I (eGCH-Tg) on murine cerebral vascular function. Endothelium targeted over-expression of GTPCH I was associated with a significant increase in levels of BH4, as well as its oxidized product, 7,8-dihydrobiopterin (7,8-BH2) in cerebral microvessels. Importantly, ratio of BH4 to 7,8-BH2, indicative of BH4 available for eNOS activation, was significantly increased in eGCH-Tg mice. However, expression of endothelial NOS, levels of nitrate/nitrite - indicative of NO production - remained unchanged between cerebral microvessels of wild-type and eGCH-Tg mice. Furthermore, increased BH4 biosynthesis neither affected production of superoxide anion nor expression of antioxidant proteins. Moreover, endothelium-specific GTPCH I overexpression did not alter intracellular levels of cGMP, reflective of NO signaling in cerebral microvessels. The obtained results suggest that, despite a significant increase in BH4 bioavailability, generation of endothelial NO in cerebral microvessels remained unchanged in eGCH-Tg mice. We conclude that under physiological conditions the levels of BH4 in the cerebral microvessels are optimal for activation of endothelial NOS and NO/cGMP signaling.
AB - Tetrahydrobiopterin (BH4) is a critical determinant of nitric oxide (NO) production by nitric oxide synthase (NOS) in the vascular endothelium and its biosynthesis is regulated by the enzymatic activity of GTP-cyclohydrolase I (GTPCH I). The present study was designed to determine the effects of endothelium-targeted overexpression of GTPCH I (eGCH-Tg) on murine cerebral vascular function. Endothelium targeted over-expression of GTPCH I was associated with a significant increase in levels of BH4, as well as its oxidized product, 7,8-dihydrobiopterin (7,8-BH2) in cerebral microvessels. Importantly, ratio of BH4 to 7,8-BH2, indicative of BH4 available for eNOS activation, was significantly increased in eGCH-Tg mice. However, expression of endothelial NOS, levels of nitrate/nitrite - indicative of NO production - remained unchanged between cerebral microvessels of wild-type and eGCH-Tg mice. Furthermore, increased BH4 biosynthesis neither affected production of superoxide anion nor expression of antioxidant proteins. Moreover, endothelium-specific GTPCH I overexpression did not alter intracellular levels of cGMP, reflective of NO signaling in cerebral microvessels. The obtained results suggest that, despite a significant increase in BH4 bioavailability, generation of endothelial NO in cerebral microvessels remained unchanged in eGCH-Tg mice. We conclude that under physiological conditions the levels of BH4 in the cerebral microvessels are optimal for activation of endothelial NOS and NO/cGMP signaling.
KW - Cerebral microvessel
KW - Endothelial nitric oxide synthase
KW - GTP-cyclohydrolase I
KW - Tetrahydrobiopterin
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U2 - 10.1016/j.brainres.2015.08.034
DO - 10.1016/j.brainres.2015.08.034
M3 - Article
C2 - 26343845
AN - SCOPUS:84948444786
VL - 1625
SP - 198
EP - 205
JO - Brain Research
JF - Brain Research
SN - 0006-8993
ER -