Editors' ChoiceVascular Medicine

Regulation from the Inside Out

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Science Translational Medicine  26 Sep 2012:
Vol. 4, Issue 153, pp. 153ec172
DOI: 10.1126/scitranslmed.3004987

A good sports team requires excellent coaching and skillful players who can execute the coach’s orders. Similarly in cells, phosphatidylinositol 3 kinase (PI3K) orchestrates cell behavior through its lipid products, which carry intracellular messages throughout the cell. Now, Yoshioka and colleagues have shown how a class II PI3K, PI3K-C2α (C2α), instructs cells to form a healthy vasculature. C2α is found in the endosome, the trans-Golgi network and clathrin-coated vesicles of epithelial, endothelial, and smooth muscle cells. By using C2α-deficient mice, Yoshioka et al. showed that this class II PI3K—specifically, C2α in endothelial cells—was essential for vascular development. After knockdown of endothelial C2α, the authors noted defective endothelial cell migration, proliferation, and tube formation. Deficient C2α also suppressed the RhoA activation induced by vascular endothelial growth factor A, impairing trafficking of vascular endothelial-cadherin (CD144) from the Golgi apparatus to intercellular junctions at the plasma membrane. This decrease in trafficking to the membrane inhibited new vessel formation, whether triggered by ischemia or by the presence of a tumor. Furthermore, depletion of C2α dramatically reduced the barrier function of the endothelium, resulting in an increased likelihood of anaphylaxis and aortic dissection.

The findings by Yoshioka et al. uncover some of the underlying mechanisms that orchestrate endothelial cell behavior. The authors reveal that the class II PI3K C2α is crucial for the formation of a healthy vascular system and for the integrity and barrier function of blood vessels. This kinase may be a potential drug target for combating vascular diseases in connection with disruption in barrier function.

K. Yoshioka et al., Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function. Nat. Med., published online 16 September 2012 (10.1038/nm.2928). [Abstract]

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