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1 Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA; Department of Anesthesiology, National Cheng Kung University Hospital, Tainan, Taiwan
2 Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
3 Division of Nephrology, Mayo Clinic, Rochester, MN, USA
* To whom correspondence should be addressed. E-mail: katusic.zvonimir{at}mayo.edu.
Shear stress, imposed on the vascular endothelium by circulating blood, critically sustains vascular synthesis of nitric oxide (NO). Endothelial NO synthase (eNOS) activity is determined by heat shock protein (Hsp) 90, caveolin-1, and the cofactor, tetrahydrobiopterin (BH4). To determine whether increased blood flow concomitantly upregulates eNOS and GTP cyclohydrolase I (GTPCH-1, the rate-limiting enzyme in BH4 biosynthesis), an aortocaval fistula model in the rat was employed wherein aortic blood flow is enhanced proximal to the fistula, but decreased distal to the fistula. Eight weeks after the creation of the aortocaval fistula, the proximal and distal aortic segments were harvested; sham-operated rats served as controls. Vasomotor function was assessed by isometric force recording. Expression of eNOS, Hsp90, caveolin-1, Akt, phosphorylated eNOS (eNOS-S1177), and GTPCH-I were determined by Western analysis. Biosynthesis of BH4 and GTPCH-1 activity were examined by HPLC. In the aortic segments exposed to increased flow, contractions to KCl and phenylephrine were reduced, whereas endothelium-dependent relaxations were not affected as compared to sham-operated or aortic segments with reduced blood flow. Expression of eNOS, caveolin-1, phosphorylated Akt and eNOS-S1177 was enhanced in aortas exposed to increased blood flow. High flow augmented levels of cGMP and BH4, and increased expression of GTPCH-I. In aggregate, these findings provide the first demonstration in vivo that coordinated vascular upregulation of eNOS and GTPCH-I accompanies increased blood flow; this induction of GTPCH-1 increases BH4 production, thereby optimizing the generation of NO by eNOS and thus the adaptive, vasorelaxant response required in sustaining increased blood flow.
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