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Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function

Nature Medicine volume 18, pages 1560–1569 (2012)Cite this article

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Abstract

The class II α-isoform of phosphatidylinositol 3-kinase (PI3K-C2α) is localized in endosomes, the trans-Golgi network and clathrin-coated vesicles; however, its functional role is not well understood. Global or endothelial-cell–specific deficiency of PI3K-C2α resulted in embryonic lethality caused by defects in sprouting angiogenesis and vascular maturation. PI3K-C2α knockdown in endothelial cells resulted in a decrease in the number of PI3-phosphate–enriched endosomes, impaired endosomal trafficking, defective delivery of VE-cadherin to endothelial cell junctions and defective junction assembly. PI3K-C2α knockdown also impaired endothelial cell signaling, including vascular endothelial growth factor receptor internalization and endosomal RhoA activation. Together, the effects of PI3K-C2α knockdown led to defective endothelial cell migration, proliferation, tube formation and barrier integrity. Endothelial PI3K-C2α deficiency in vivo suppressed postischemic and tumor angiogenesis and diminished vascular barrier function with a greatly augmented susceptibility to anaphylaxis and a higher incidence of dissecting aortic aneurysm formation in response to angiotensin II infusion. Thus, PI3K-C2α has a crucial role in vascular formation and barrier integrity and represents a new therapeutic target for vascular disease.

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Figure 1: Endothelial C2α is necessary for developmental angiogenesis.
Figure 2: C2α is required for postnatal retinal angiogenesis.
Figure 3: Tube formation, cell migration and RhoA activation are impaired in C2α-depleted HUVEC.
Figure 4: Endosomal transport, VE-cadherin assembly at cell junctions and the activation of endosomal RhoA are impaired in C2α-depleted endothelial cells.
Figure 5: Targeted deletion of endothelial C2α reduces postischemic and tumor angiogenesis.
Figure 6: C2α deficiency causes vascular hyperpermeability and dissecting aortic aneurysm formation in vivo.

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Acknowledgements

We thank K. Mitsumori for comments on the histological study. We thank N. Mochizuki and K. Ando for assistance with the FRET imaging analysis. We thank N. Furusawa, K. Sunagawa and E. Kaneko for assistance with live-cell imaging using a Yokogawa confocal microscope system. We also thank Y. Ohta and T. Murakawa for technical assistance and T. Hirose for administrative assistance. C2α complementary DNA was obtained from J. Domin (Imperial College London). GFP-2 × FYVE and mRFP-2 × FYVE expression vectors were obtained from H. Stenmark (Oslo University Hospital) and Y. Ohsumi (Tokyo Institute of Technology), respectively. VE-cadherin-GFP expression vectors were obtained from N. Mochizuki (National Cerebral and Cardiovascular Center). The pRaichu-RhoA probe was obtained from M. Matsuda (Kyoto University). GFP-RhoAAsn19 and GFP-RhoAVal14 expression vectors were obtained from F. Valderrama (King's College London). This work was supported in part by grants-in-aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology, the Japan Society for the Promotion of Science (to K. Yoshioka, N. Takuwa, Y.O. and Y.T.), the Honjin Foundation, the Mitsubishi Pharma Research Foundation and the SENSIN Medical Research Foundation (to K. Yoshioka).

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Author notes

  1. Kazuaki Yoshioka and Kotaro Yoshida: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Japan

    Kazuaki Yoshioka, Kotaro Yoshida, Hong Cui, Noriko Takuwa, Yasuo Okamoto, Wa Du, Xun Qi, Sho Aki, Hidekazu Miyazawa, Kuntal Biswas, Chisa Nagakura & Yoh Takuwa

  2. Department of Radiology, Kanazawa University School of Medicine, Kanazawa, Japan

    Kotaro Yoshida & Osamu Matsui

  3. Department of Histology and Embryology, Kanazawa University School of Medicine, Kanazawa, Japan

    Tomohiko Wakayama & Shoichi Iseki

  4. Department of Health and Medical Sciences, Ishikawa Prefectural Nursing University, Kahoku, Japan

    Noriko Takuwa

  5. Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan

    Ken Asanuma & Takehiko Sasaki

  6. Division of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan

    Kazushi Sugihara & Masahide Asano

  7. Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

    Masaya Ueno & Nobuyuki Takakura

  8. Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA

    Robert J Schwartz

  9. Department of Medical Biochemistry, Tohoku University School of Medicine, Sendai, Japan

    Hiroshi Okamoto

  10. Research Center for Biosignal, Akita University, Akita, Japan

    Takehiko Sasaki

  11. Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Muenster, Germany

    Ralf H Adams

  12. University of Muenster, Faculty of Medicine, Muenster, Germany

    Ralf H Adams

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  1. Kazuaki Yoshioka
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Contributions

K. Yoshioka designed the experiments, performed characterization of the developmental and retinal angiogenesis of the conditional knockout mice and most of the in vitro studies and analyzed the data with assistance from N. Takuwa, Y.O., W.D., S.A., H.M., C.N., K.B., M.U., N. Takakura and O.M. K.A. and T.S. analyzed the cellular content of phosphoinositides. K. Yoshida performed in vivo angiogenenesis experiments with K. Yoshioka, performed tumor implantation and aneurysm experiments and interpreted the results. H.C. performed the anaphylaxis experiments. W.D. performed the in vivo permeability study. X.Q. and Y.O. performed and interpreted the results of the ischemic angiogenesis model. T.W. and S.I. performed and interpreted the results of electron microscopy. K.S., M.A., N. Takuwa, R.J.S., H.O. and R.H.A. generated mouse mutants. K. Yoshioka and Y.T. planned and supervised the experiments, arranged the figures and wrote the manuscript. M.A. and N. Takuwa participated in writing the manuscript (M.A. wrote part of the Online Methods, and N. Takuwa wrote the Abstract, Introduction and Results sections).

Corresponding author

Correspondence to Yoh Takuwa.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–20, Supplementary Tables 1–7 and Supplementary Methods (PDF 5179 kb)

Supplementary Video 1

Time-lapse imaging of GFP-C2α and mRFP-2xFYVE in HUVEC. (MOV 1720 kb)

Supplementary Video 2

Trafficking of the intracellular GFP-2xFYVE-positive endosomes in control HUVEC. (MOV 1755 kb)

Supplementary Video 3

Trafficking of the intracellular GFP-2xFYVE-positive endosomes in C2α-depleted HUVEC. (MOV 1880 kb)

Supplementary Video 4

Trafficking of VE-cadherin-GFP in control HUVEC. (MOV 3672 kb)

Supplementary Video 5

Trafficking of VE-cadherin-GFP in C2α-depleted HUVEC. (MOV 2159 kb)

Supplementary Video 6

Trafficking of VE-cadherin-GFP in adeno-RhoAN19-infected HUVEC. (MOV 839 kb)

Supplementary Video 7

RhoA FRET imaging in control HUVEC. (MOV 1741 kb)

Supplementary Video 8

RhoA FRET imaging in C2α-depleted HUVEC. (MOV 1807 kb)

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Yoshioka, K., Yoshida, K., Cui, H. et al. Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function. Nat Med 18, 1560–1569 (2012). https://doi.org/10.1038/nm.2928

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