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Cyclic Stretch Alters Vascular Reactivity of Mouse Aortic Segments.

ABSTRACT: Large, elastic arteries buffer the pressure wave originating in the left ventricle and are constantly exposed to higher amplitudes of cyclic stretch (10%) than muscular arteries (2%). As a crucial factor for endothelial and smooth muscle cell function, cyclic stretch has, however, never been studied in ex vivo aortic segments of mice. To investigate the effects of cyclic stretch on vaso-reactivity of mouse aortic segments, we used the Rodent Oscillatory Tension Set-up to study Arterial Compliance (ROTSAC). The aortic segments were clamped at frequencies of 6-600 bpm between two variable preloads, thereby mimicking dilation as upon left ventricular systole and recoiling as during diastole. The preloads corresponding to different transmural pressures were chosen to correspond to a low, normal or high amplitude of cyclic stretch. At different time intervals, cyclic stretch was interrupted, the segments were afterloaded and isometric contractions by ?1-adrenergic stimulation with 2 ?M phenylephrine in the absence and presence of 300 ?M L-NAME (eNOS inhibitor) and/or 35 ?M diltiazem (blocker of voltage-gated Ca2+ channels) were measured. As compared with static or cyclic stretch at low amplitude (<10 mN) or low frequency (0.1 Hz), cyclic stretch at physiological amplitude (>10 mN) and frequency (1-10 Hz) caused better ex vivo conservation of basal NO release with time after mounting. The relaxation of PE-precontracted segments by addition of ACh to stimulate NO release was unaffected by cyclic stretch. In the absence of basal NO release (hence, presence of L-NAME), physiological in comparison with aberrant cyclic stretch decreased the baseline tension, attenuated the phasic contraction by phenylephrine in the absence of extracellular Ca2+ and shifted the smaller tonic contraction more from a voltage-gated Ca2+ channel-mediated to a non-selective cation channel-mediated. Data highlight the need of sufficient mechanical activation of endothelial and vascular smooth muscle cells to maintain basal NO release and low intracellular Ca2+ in the smooth muscle cells in large arteries. Both phenomena may play a vital role in maintaining the high compliance of large arteries.

SUBMITTER: Leloup A

PROVIDER: S-EPMC5674939 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Cyclic Stretch Alters Vascular Reactivity of Mouse Aortic Segments.

Leloup Arthur A De Moudt Sofie S Van Hove Cor C Fransen Paul P

Frontiers in physiology 20171030

Large, elastic arteries buffer the pressure wave originating in the left ventricle and are constantly exposed to higher amplitudes of cyclic stretch (10%) than muscular arteries (2%). As a crucial factor for endothelial and smooth muscle cell function, cyclic stretch has, however, never been studied in <i>ex vivo</i> aortic segments of mice. To investigate the effects of cyclic stretch on vaso-reactivity of mouse aortic segments, we used the Rodent Oscillatory Tension Set-up to study Arterial Co ...[more]

PMID: 29163203

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Project description: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-α-converting enzyme (TACE) or N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT; 20 μmol/l) to inhibit γ-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.

Dataset Information

Cyclic Stretch Alters Vascular Reactivity of Mouse Aortic Segments.

Publications

Cyclic Stretch Alters Vascular Reactivity of Mouse Aortic Segments.

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