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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 13, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm103
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Rapamycin modulates the eNOS versus shear stress relationship

Caroline Cheng1, Dennie Tempel1, Angela Oostlander2, Frank Helderman1, Frank Gijsen1, Jolanda Wentzel1, Rien van Haperen2, David B. Haitsma1, Patrick W. Serruys1, Anton F.W. van der Steen1, Rini de Crom2,3 and Rob Krams1,4,

1 Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands
2 Department of Cell Biology & Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
3 Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
4 Dept. Bioengineering, Imperial College London, UK

Address for correspondence: R. Krams, M.D. Ph.D. Dept. Bioengineering, Room E552 Imperial College London South Kensington Campus London SW7 2AZ United Kingdom Telephone: +44-2075941473E-mail: r.krams{at}imperial.ac.uk

Aims: Studies in animals and patients indicate that rapamycin affects vasodilatation differently in outer and inner curvatures of blood vessels. We evaluated in this study whether rapamycin affects endothelial nitric oxide synthase (eNOS) responsiveness to shear stress under normo- and hypercholesteremic conditions to explain these findings.

Methods: Shear stress levels were varied over a large range of values in carotid arteries of transgenic mice expressing human eNOS fused to enhanced green fluorescence protein. The mice were divided into control, low-dose rapamycin (3 µg/kg/day), and high-dose rapamycin (3 mg/kg/day) groups and into normocholesteremic and hypercholesteremic (ApoE-/- on high cholesterol diet for 3-4 weeks) groups. The effect of rapamycin treatment on eNOS was evaluated by quantification of eNOS expression and of intracellular protein levels by en face confocal microscopy. A sigmoid curve fit was used to described these data.

Results: The efficacy of treatment was confirmed by measurement of rapamycin serum levels (2.0 ± 0.5 ng/ml), and of p27kip1 expression in vascular tissue (increased by 2.4±0.5 fold). In control carotid arteries, eNOS expression increased by 1.8±0.3 fold in response to rapamycin. In the treated vessels, rapamycin reduced maximal eNOS expression at high shear stress levels (> 5 Pa) in a dose-dependent way and shifted the sigmoid curve to the right. Hypercholesteremia had a tendency to increase the leftward shift and the reduction in maximal eNOS expression (p=0.07).

Conclusion: Rapamycin is associated with high eNOS in low shear regions, i.e. in atherogenic regions, protecting these regions against atherosclerosis, and is associated with a reduction of eNOS at high shear stress affecting vasomotion in these regions.

Time for primary review: 22


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