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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1223.)
© 2004 American Heart Association, Inc.

Vascular Biology

Microtubules Regulate Angiotensin II Type 1 Receptor and Rac1 Localization in Caveolae/Lipid Rafts

Role in Redox Signaling

Lian Zuo; Masuko Ushio-Fukai; Lula L. Hilenski; R. Wayne Alexander

From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga.

Correspondence to Masuko Ushio-Fukai, PhD, Division of Cardiology, Emory University School of Medicine, 1639 Pierce Drive, Room 319, Atlanta, GA 30322. E-mail mfukai{at}emory.edu

Objective— Microtubules are important in signal transduction temporal–spatial organization. Full expression of angiotensin II (Ang II) signaling in vascular smooth muscle cells (VSMCs) is dependent on the reactive oxygen species (ROS) derived from nicotinamide-adenine dinucleotide phosphate (NAD(P)H) oxidase and the dynamic association of the Ang II type 1 receptor (AT₁R) with caveolae/lipid rafts. Translocation of the small GTPase Rac1 to the plasma membrane is an essential step for activation of NAD(P)H oxidase; however, its precise localization in the plasma membrane after agonist stimulation and how it is targeted are unknown. We hypothesized that microtubules are involved in regulating multiphasic Ang II signaling events in VSMC.

Methods and Results— We show that Ang II promotes Rac1 and AT₁R trafficking into caveolae/lipid rafts, which is blocked by disruption of microtubules with nocodazole. As a consequence, nocodazole significantly inhibits Ang II–stimulated H₂O₂ production, its downstream ROS-dependent epidermal growth factor receptor transactivation, Akt phosphorylation, and vascular hypertrophy without affecting Rac1 activation or ROS-independent extracellular signal-regulated kinase 1/2 phosphorylation.

Conclusions— These results suggest that proper Rac1 and AT₁R trafficking into caveolae/lipid rafts requires the integrity of microtubules and provide insight into the essential role of microtubules for the spatial–temporal organization of ROS-dependent and caveolae/lipid rafts–dependent AT₁R signaling linked to vascular hypertrophy.

The role of microtubules in angiotensin II (Ang II) signaling remains unknown. We demonstrate that Ang II promotes Rac1 and Ang II type 1 receptor trafficking into the caveolae/lipid rafts, which requires the integrity of microtubules. We also found that intact microtubules mediate Ang II–stimulated H₂O₂ production, its downstream EGF-R transactivation, Akt phosphorylation, and vascular hypertrophy.

Key Words: microtubules • angiotensin II • reactive oxygen species • caveolae • vascular smooth muscle

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