J Physiol Volume 558, Number 2, 479-488, July 15, 2004 DOI: 10.1113/jphysiol.2004.065334
Sequential activation of RhoA and FAK/paxillin leads to ATP release and actin reorganization in human endothelium
Masakazu Hirakawa,
Masahiro Oike,
Yuji Karashima and
Yushi Ito
Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
We have investigated the cellular mechanisms of mechanical stress-induced immediate responses in human umbilical vein endothelial cells (HUVECs). Hypotonic stress (HTS) induced ATP release, which evoked a Ca2+ transient, followed by actin reorganization within a few minutes, in HUVECs. Disruption of the actin cytoskeleton did not suppress HTS-induced ATP release, and inhibition of the ATP-mediated Ca2+ response did not affect actin reorganization, thereby indicating that these two responses are not interrelated. ATP release and actin reorganization were also induced by lysophosphatidic acid (LPA). HTS and LPA induced membrane translocation of RhoA, which occurs when RhoA is activated, and tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin. Tyrosine kinase inhibitors (herbimycin A or tyrphostin 46) inhibited both HTS- and LPA-induced ATP release and actin reorganization, but did not affect RhoA activation. In contrast, Rho-kinase inhibitor (Y27632) inhibited all of the HTS- and LPA-induced responses. These results indicate that the activation of the RhoA/Rho-kinase pathway followed by tyrosine phosphorylation of FAK and paxillin leads to ATP release and actin reorganization in HUVECs. Furthermore, the fact that HTS and LPA evoke exactly the same intracellular signals and responses suggests that even these immediate mechanosensitive responses are in fact not mechanical stress-specific.
(Received 25 March 2004;
accepted after revision 19 May 2004;
first published online 21 May 2004)
Corresponding author M. Oike: Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Email: moike{at}pharmaco.med.kyushu-u.ac.jp
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