Central Role of Calcium-Dependent Tyrosine Kinase PYK2 in Endothelial Nitric Oxide Synthase–Mediated Angiogenic Response and Vascular Function
Abstract
Background— The involvement of Ca 2+ -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 Ca 2+ mobilization and Ca 2+ -independent Akt activation were markedly decreased in the PYK2-deficient aortic endothelial cells, whereas the Ca 2+ -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 PLCγ1 and phosphorylation of 783 Tyr-PLCγ1 also were abolished by PYK2 deficiency. Conclusion— These findings demonstrate that PYK2 is closely involved in receptor- or ischemia-activated signaling events via Src/PLCγ1 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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NOX4 appears to be constitutively active in the presence of p22phox without the participation of cytosolic proteins.
“NOX4 appears to be constitutively active in the presence of p22phox without the participation of cytosolic proteins (24, 627).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [627]
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Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
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Beck, T. N., Nicolas, E., Kopp, M. C., & Golemis, E. A. (2014) · Oncoscience · doi:10.18632/oncoscience.64 · Cited by 50 · see citing works
- Authors
- Matsui, A., Okigaki, M., Amano, K., Adachi, Y., Jin, D., Takai, S., Yamashita, T., Kawashima, S., Kurihara, T., Miyazaki, M., Tateishi, K., Matsunaga, S., Katsume, A., Honshou, S., Takahashi, T., Matoba, S., Kusaba, T., Tatsumi, T., & Matsubara, H.
- Affiliations
- Kansai Medical University (JP)
- ORCID
- Venue
- Circulation
- Published
- 2007-08-28
- Volume
- 116
- Issue
- 9
- Pages
- 1041-1051
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2159346219
- Cited by
- 47
- References
- 39
- Citations by year
- 2026: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 1 · 2017: 6 · 2016: 4 · 2015: 3 · 2014: 5 · 2013: 1 · 2012: 5
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Pyk2, endothelial nitric oxide synthase, angiogenesis, vascular function, hindlimb ischemia, endothelial progenitor cells, vascular endothelial growth factor, Src kinase, PI3K/Akt signaling, PLCγ1, actin cytoskeleton, Rac1, cyclic GMP, neovascularization
- MeSH terms
- Analysis of Variance, Animals, Calcium, Enzyme Activation, Heart, Hindlimb, Ischemia, Phosphorylation, Vasodilation, Signal Transduction, Mice, Knockout, Neovascularization, Physiologic, Vascular Endothelial Growth Factor A, Oncogene Protein v-akt, Mice, Focal Adhesion Kinase 2, Nitric Oxide Synthase Type III
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