[OP.8C.02] SENESCENCE INCREASES VASCULAR SMOOTH MUSCLE CONTRACTIONS THROUGH INCREASED RHO KINASE ACTIVITY IN FEMALE MOUSE AORTA

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Abstract

Objective:

In vascular smooth muscle the Rho signaling pathway is highly activated in a variety of vascular diseases. Our aim was to check the involvement of Rho kinase (ROCK) on the increased vascular contractions induced by ageing in female mouse aorta.

Design and method:

Female senescence-accelerated mice (SAMP8, n = 21) or the control, SAM-resistant (SAMR1, n = 21), were divided in three groups: 3-, 6-, and 10-months old. Vascular rings (4 mm long) from thoracic aorta were mounted for isometric recording of tension. Concentration-response curves to KCl (5–120 mM) and U46619 (10-9–3x10-7 M), a stable analogue of thromboxane A2, were performed in the absence and in the presence of Y-27632 (10-5 M) or hydroxyfasudil (10-5 M), ROCK inhibitors. To study the effects of senescence on calcium-induced contractions, artery rings were incubated in calcium-free solution containing 60 mM KCl and concentration-response curves to calcium chloride (CaCl2, 10-6–3x10 3 M) were determined in the absence and in the presence of the inhibitors.

Results:

KCl- and U46619-induced contractions were greater (P < 0.05) in aorta from SAMP8 compared with SAMR1 at 6- and 10-months old groups. In all arteries tested, the ROCK inhibitors Y-27632 or hydroxyfasudil significantly depressed the contractions to KCl and U46619. Interestingly, the increased contraction induced by senescence were inhibited by Y-27632 or hydroxyfasudil. In arteries incubated in Ca2+-free solution containing 60 mM KCl, addition of CaCl2 elicited a concentration-dependent contractile response. In the SAMP8, maximal responses to CaCl2 were increased but pD2 values were not significantly different (P > 0.05). In vessels exposed to Ca2+-free solution containing 60 mM KCl, Y-27632 or hydroxyfasudil induced a significant decrease of the maximal contraction induced by CaCl2 and the potentiation induced by senescence on the CaCl2 response curves was abolished.

Conclusions:

ROCK activity is involved in the increased response to thromboxane A2 induced by senescence in aged female mouse. Accordingly, Rho kinase inhibitors may have therapeutic potential for preventing vascular disease induced by ageing.

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