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J Appl Physiol 101: 1751-1759, 2006; doi:10.1152/japplphysiol.00138.2006
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Impaired shear stress-induced nitric oxide production through decreased NOS phosphorylation contributes to age-related vascular stiffness

Kevin G. Soucy,1 Sungwoo Ryoo,2 Alexandre Benjo,2 Hyun Kyo Lim,2,4 Gaurav Gupta,1 Jayson S. Sohi,1 Jeremy Elser,1 Miguel A. Aon,3 Daniel Nyhan,2 Artin A. Shoukas,1 and Dan E. Berkowitz1,2

Departments of 1Biomedical Engineering and 2Anesthesiology/Critical Care Medicine and 3Institute of Molecular Cardiobiology, Johns Hopkins Medical Institutions, Baltimore, Maryland; and 4Department of Anesthesiology and Pain Medicine, Yonsei University, Wonju, Korea

Submitted 2 February 2006 ; accepted in final form 3 August 2006

Endothelial dysfunction and increased arterial stiffness contribute to multiple vascular diseases and are hallmarks of cardiovascular aging. To investigate the effects of aging on shear stress-induced endothelial nitric oxide (NO) signaling and aortic stiffness, we studied young (3–4 mo) and old (22–24 mo) rats in vivo and in vitro. Old rat aorta demonstrated impaired vasorelaxation to acetylcholine and sphingosine 1-phosphate, while responses to sodium nitroprusside were similar to those in young aorta. In a customized flow chamber, aortic sections preincubated with the NO-sensitive dye, 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate, were subjected to steady-state flow with shear stress increase from 0.4 to 6.4 dyn/cm2. In young aorta, this shear step amplified 4-amino-5-methylamino-2',7'-difluorofluorescein fluorescence rate by 70.6 ± 13.9%, while the old aorta response was significantly attenuated (23.6 ± 11.3%, P < 0.05). Endothelial NO synthase (eNOS) inhibition, by NG-monomethyl-L-arginine, abolished any fluorescence rate increase. Furthermore, impaired NO production was associated with a significant reduction of the phosphorylated-Akt-to-total-Akt ratio in aged aorta (P < 0.05). Correspondingly, the phosphorylated-to-total-eNOS ratio in aged aortic endothelium was markedly lower than in young endothelium (P < 0.001). Lastly, pulse wave velocity, an in vivo measure of vascular stiffness, in old rats (5.99 ± 0.191 m/s) and in N{omega}-nitro-L-arginine methyl ester-treated rats (4.96 ± 0.118 m/s) was significantly greater than that in young rats (3.64 ± 0.068 m/s, P < 0.001). Similarly, eNOS-knockout mice demonstrated higher pulse wave velocity than wild-type mice (P < 0.001). Thus impaired Akt-dependent NO synthase activation is a potential mechanism for decreased NO bioavailability and endothelial dysfunction, which likely contributes to age-associated vascular stiffness.

serine/threonine kinase Akt; endothelial dysfunction; mechanotransduction; nitric oxide synthase; aging


Address for reprint requests and other correspondence: D. E. Berkowitz, Johns Hopkins Medical Institutions, Anesthesiology & Critical Care Medicine, 600 N. Wolfe St., Tower 711, Baltimore, MD 21287 (e-mail: dberkow1{at}jhmi.edu)




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