Published Online
on August 13, 2007

A more recent version of this article appeared on August 28, 2007

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Submitted on August 9, 2005
Accepted on June 12, 2007

Central Role of Calcium-Dependent Tyrosine Kinase PYK2 in Endothelial Nitric Oxide Synthase–Mediated Angiogenic Response and Vascular Function

Akihiro Matsui MD, Mitsuhiko Okigaki MD, PhD^*, Katsuya Amano MD, PhD, Yasushi Adachi MD, PhD, Denan Jin MD, PhD, Shinji Takai PhD, Tomoya Yamashita MD, PhD, Seinosuke Kawashima MD, PhD, Tatsuya Kurihara PhD, Mizuo Miyazaki MD, PhD, Kento Tateishi MD, PhD, Shinsaku Matsunaga MD, Asako Katsume MD, Shoken Honshou MD, Tomosaburo Takahashi MD, PhD, Satoaki Matoba MD, PhD, Tetsuro Kusaba MD, Tetsuya Tatsumi MD, PhD, and Hiroaki Matsubara MD, PhD

From the Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto (A.M., M.O., K.T., S.M., A.K., S.H., T. Takahashi, S.M., T. Kusaba, T. Tatsumi, H.M.); Departments of Internal Medicine II (K.A.) and Pathology I (Y.A.), Kansai Medical University, Osaka; Department of Pharmacology, Osaka Medical College, Takatsuki (D.J., S.T., M.M.); Division of Cardiovascular and Respiratory Medicine, Kobe University School of Medicine, Kobe (T.Y., S.K.); and Daiichi Asubio Pharma Co Ltd Biomedical Research Laboratories, Osaka (T. Kurihara), Japan.

^* To whom correspondence should be addressed. E-mail: okigakim{at}koto.kpu-m.ac.jp.

Background—The involvement of Ca²⁺-dependent tyrosine kinase PYK2 in the Akt/endothelial NO synthase pathway remains to be determined.

Methods and Results—Blood flow recovery and neovessel formation after hind-limb ischemia were impaired in PYK2^-/- mice with reduced mobilization of endothelial progenitors. Vascular endothelial growth factor (VEGF)–mediated cytoplasmic Ca²⁺ mobilization and Ca²⁺-independent Akt activation were markedly decreased in the PYK2-deficient aortic endothelial cells, whereas the Ca²⁺-independent AMP-activated protein kinase/protein kinase-A pathway that phosphorylates endothelial NO synthase was not impaired. Acetylcholine-mediated aortic vasorelaxation and cGMP production were significantly decreased. Vascular endothelial growth factor–dependent migration, tube formation, and actin cytoskeletal reorganization associated with Rac1 activation were inhibited in PYK2-deficient endothelial cells. PI3-kinase is associated with vascular endothelial growth factor–induced PYK2/Src complex, and inhibition of Src blocked Akt activation. The vascular endothelial growth factor–mediated Src association with PLC1 and phosphorylation of ⁷⁸³Tyr-PLC1 also were abolished by PYK2 deficiency.

Conclusion—These findings demonstrate that PYK2 is closely involved in receptor- or ischemia-activated signaling events via Src/PLC1 and Src/PI3-kinase/Akt pathways, leading to endothelial NO synthase phosphorylation, and thus modulates endothelial NO synthase–mediated vasoactive function and angiogenic response.

Key words: angiogenesis • endothelium • nitric oxide synthase • signal transduction • vasodilation

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