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(Circulation. 2007;116:1041-1051.)
© 2007 American Heart Association, Inc.

Vascular Medicine

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; 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.

Correspondence to Mitsuhiko Okigaki, MD, Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, 602–8566, Japan. E-mail okigakim{at}koto.kpu-m.ac.jp

Received August 9, 2005; accepted June 12, 2007.

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.

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