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Caveolin-1 abolishment attenuates the myogenic response in murine cerebral arteries

Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 5 June 2006 ; accepted in final form 7 November 2006

Intravascular pressure-induced vasoconstriction (the "myogenic response") is intrinsic to smooth muscle cells, but mechanisms that underlie this response are unresolved. Here we investigated the physiological function of arterial smooth muscle cell caveolae in mediating the myogenic response. Since caveolin-1 (cav-1) ablation abolishes caveolae formation in arterial smooth muscle cells, myogenic mechanisms were compared in cerebral arteries from control (cav-1^+/+) and cav-1-deficient (cav-1^–/–) mice. At low intravascular pressure (10 mmHg), wall membrane potential, intracellular calcium concentration ([Ca²⁺]_i), and myogenic tone were similar in cav-1^+/+ and cav-1^–/– arteries. In contrast, pressure elevations to between 30 and 70 mmHg induced a smaller depolarization, [Ca²⁺]_i elevation, and myogenic response in cav-1^–/– arteries. Depolarization induced by 60 mM K⁺ also produced an attenuated [Ca²⁺]_i elevation and constriction in cav-1^–/– arteries, whereas extracellular Ca²⁺ removal and diltiazem, an L-type Ca²⁺ channel blocker, similarly dilated cav-1^+/+ and cav-1^–/– arteries. N-nitro-L-arginine, an nitric oxide synthase inhibitor, did not restore myogenic tone in cav-1^–/– arteries. Iberiotoxin, a selective Ca²⁺-activated K⁺ (K_Ca) channel blocker, induced a similar depolarization and constriction in pressurized cav-1^+/+ and cav-1^–/– arteries. Since pressurized cav-1^–/– arteries are more hyperpolarized and this effect would reduce K_Ca current, these data suggest that cav-1 ablation leads to functional K_Ca channel activation, an effect that should contribute to the attenuated myogenic constriction. In summary, data indicate that cav-1 ablation reduces pressure-induced depolarization and depolarization-induced Ca²⁺ influx, and these effects combine to produce a diminished arterial wall [Ca²⁺]_i elevation and constriction.

calcium-activated potassium channels; membrane depolarization; arterial wall calcium

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