Published online before print January 24, 2005, doi: 10.1161/01.CIR.0000154548.16191.2F
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(Circulation. 2005;111:643-649.)
© 2005 American Heart Association, Inc.
Molecular Cardiology |
Differential Regulation of Vascular Focal Adhesion Kinase by Steady Stretch and Pulsatility
From INSERM U541, Hôpital Lariboisière, Paris, France.
Correspondence to Dr Stéphanie Lehoux, INSERM U541, Hôpital Lariboisière, 41, Boulevard de la Chapelle, 75010 Paris, France. E-mail lehoux{at}larib.inserm.fr
Received May 26, 2004; revision received October 13, 2004; accepted October 15, 2004.
Background— In vivo tensile strain in arteries comprises 2 components: steady stretch and pulsatile stretch. However, little attention has been paid to the differential transduction of these stimuli in whole vessels.
Methods and Results— Using rabbit aortas maintained in organ culture for 24 hours, we found that focal adhesion kinase (FAK) was strongly activated by high intraluminal pressure (150 mm Hg), as evidenced by increased phosphorylation (P<0.01) of tyrosine residues Tyr-397 (3.06±0.17-fold), Tyr-407 (3.71±0.65-fold), Tyr-861 (1.92±0.33-fold), and Tyr-925 (2.41±0.39-fold), compared with 80 mm Hg controls. Immunohistochemistry showed positive staining for these phosphotyrosines in the endothelium and innermost smooth muscle cell layers. Total FAK phosphorylation was reduced in vessels at 150 mm Hg by treatment with the Src family kinase inhibitor PP2 or with the integrin–extracellular matrix interaction–blocking RGD peptide, attaining 1.75±0.22-fold and 2.00±0.19-fold, respectively (P<0.05), compared with 3.07±0.38-fold (P<0.001) in untreated vessels. PP2 prevented phosphorylation of Tyr-407 and Tyr-925, whereas RGD peptide abolished phosphorylation of Tyr-397 and Tyr-407. PP2 and RGD peptide also inhibited high pressure–induced binding of FAK with the effector Grb2 and blocked activation of extracellular regulated kinase (ERK) 1/2 in vessels at 150 mm Hg. In contrast, 10% cyclic stretch in aortas did not induce significant FAK phosphorylation relative to nonpulsatile controls. Furthermore, although ERK1/2 was activated in vessels exposed to pulsatility, it was not blocked by PP2 or RGD peptide treatment.
Conclusions— Our results demonstrate that (1) steady and cyclic modes of stretch are transduced differently in the aorta, the former implicating FAK, the latter not, and (2) Src and integrins are involved in steady pressure–induced FAK.
Key Words: mechanics • signal transduction • remodeling • hypertension • arteries
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