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Cyclic stretch stimulates vascular smooth muscle cell alignment by redox-dependent activation of Notch3.

Zhu J-H; Chen C-L; Flavahan S; Harr J; Su B; Flavahan NA
Am J Physiol Heart Circ Physiol 2011 May; 300(5):H1770-H1780
Mice deficient in Notch3 have defects in arterial vascular smooth muscle cell (VSMC) mechanosensitivity, including impaired myogenic responses and autoregulation, and inappropriate VMSC orientation. Experiments were performed to determine if Notch3 is activated by mechanical stimulation and contributes to mechanosensitive responses of VSMCs, including cell realignment. Cyclic, uniaxial stretch (10%, 1 Hz) of human VSMCs caused Notch3 activation, demonstrated by a stretch-induced increase in hairy and enhancer of split 1/hairy-related transcription factor-1 expression, translocation of Notch3 to the nucleus, and a decrease in the Notch3 extracellular domain. These effects were prevented by inhibiting the expression [small interfering (si)RNA] or proteolytic activation of Notch3 {N-(R)-[2-(hydroxyaminocarbonyl)methyl]-4-methylpentanoyl-l-naphthylalanyl-l-alanine-2-aminoethyl amide (TAPI-1; 50 µmol/l) to inhibit TNF-a-converting enzyme (TACE) or N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT; 20 µmol/l) to inhibit ?-secretase}. Stretch increased the activity of ROS within VSMCs, determined using dichlorodihydrofluorescein fluorescence. Catalase (1,200 U/ml), which degrades H2O2, inhibited the stretch-induced activation of Notch3, whereas in nonstretched cells, increasing H2O2 activity [H2O2 or manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin] caused activation of Notch3. Stretch increased the activity of TACE, which was prevented by catalase. Stretch-induced activation of p38 MAPK in VSMCs was inhibited either by catalase or by inhibiting Notch3 expression (siRNA). Stretch caused VSMCs to realign perpendicular to the direction of the mechanical stimulus, which was significantly inhibited by catalase or by inhibiting the expression (siRNA) or activation of Notch3 (TAPI-1 or DAPT). Therefore, cyclic uniaxial stretch activates Notch3 signaling through a ROS-mediated mechanism, and the presence of Notch3 is necessary for proper stretch-induced cell alignment in VSMCs. This mechanism may contribute to the physiological role of Notch3 in mediating developmental maturation of VSMCs.
Blood-vessels; Cell-biology; Cell-function; Cell-transformation; Circulatory-system; Genes; Hormone-activity; Laboratory-animals; Laboratory-testing; Motion-studies; Muscle-cells; Vasoactive-agents; Author Keywords: tumor necrosis factor-alpha-converting enzyme; hydrogen peroxide; p38 mitogen-activated protein kinase
Jianhong Zhu, Dept. of Preventive Medicine, Wenzhou Medical College, Chashan Campus, Wenzhou, Zhejiang 325035, People's Republic of China
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American Journal of Physiology - Heart and Circulatory Physiology
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Jonhs Hopkins University
Page last reviewed: March 18, 2022
Content source: National Institute for Occupational Safety and Health Education and Information Division