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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2123.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Ninein Is Expressed in the Cytoplasm of Angiogenic Tip-Cells and Regulates Tubular Morphogenesis of Endothelial Cells

Taro Matsumoto; Petter Schiller; Lothar C. Dieterich; Fuad Bahram; Yuji Iribe; Ulf Hellman; Charlotte Wikner; Gordon Chan; Lena Claesson-Welsh; Anna Dimberg

From the Department of Genetics and Pathology (T.M., P.S., L.C.D., F.B., C.W., L.C.-W., A.D.), Uppsala University, Rudbeck Laboratory, Sweden; the Division of Cell Regeneration and Transplantation, Advanced Medical Research Center (T.M., Y.I.), Nihon University School of Medicine, Tokyo, Japan; the Ludwig Institute for Cancer Research, Uppsala Branch, Biomedical Center (U.H.), Uppsala, Sweden; and the Department of Oncology (G.C.), University of Alberta, Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.

Correspondence to Anna Dimberg, Department of Genetics and Pathology, Rudbeck Laboratory, S-751 85 Uppsala, Sweden. E-mail Anna.Dimberg{at}genpat.uu.se

Objective— Angiogenesis is an integral part of many physiological processes but may also aggravate pathological conditions such as cancer. Development of effective angiogenesis inhibitors requires a thorough understanding of the molecular mechanisms regulating vessel formation. The aim of this project was to identify proteins that regulate tubular morphogenesis of endothelial cells.

Methods and Results— Phosphotyrosine-dependent affinity-purification and mass spectrometry showed tyrosine phosphorylation of ninein during tubular morphogenesis of endothelial cells. Ninein was recently identified as a centrosomal microtubule-anchoring protein. Our results show that ninein is localized in the cytoplasm in endothelial cells, and that it is highly expressed in the vasculature in normal and pathological human tissues. Using embryoid bodies as a model of vascular development, we found that ninein is abundantly expressed in the cytoplasm of endothelial cells during sprouting angiogenesis, in particular in the sprouting tip-cell. In accordance, siRNA-dependent silencing of ninein in endothelial cells inhibited tubular morphogenesis.

Conclusions— In this study, we show that ninein is expressed in developing vessels and in endothelial tip cells, and that ninein is critical for formation of the vascular tube. These data strongly implicate ninein as an important new regulator of angiogenesis.

Proteins orchestrating morphological changes accompanying formation of the vascular tube constitute new targets for antiangiogenic therapy. In this study, we identify the microtubule-anchoring protein ninein as an important new regulator of tubular morphogenesis of endothelial cells. This is the first report of a functional role of ninein in angiogenesis.

Key Words: ninein • angiogenesis • tubular morphogenesis • microtubule • endothelial

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