The Journal of Experimental Medicine
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Published 2 December 2002. doi:10.1084/jem.20021244
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© Rockefeller University Press, 0022-1007/2002/12/1497/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 11, December 2, 2002 1497-1506

Vascular Permeability Factor/Vascular Endothelial Growth Factor Induces Lymphangiogenesis as well as Angiogenesis

Janice A. Nagy, Eliza Vasile, Dian Feng, Christian Sundberg, Lawrence F. Brown, Michael J. Detmar, Joel A. Lawitts, Laura Benjamin, Xiaolian Tan, Eleanor J. Manseau, Ann M. Dvorak and Harold F. Dvorak

Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, and the Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02215

Address correspondence to Harold F. Dvorak, Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Phone: 617-667-4343; Fax: 617-667-2943; E-mail: hdvorak{at}caregroup.harvard.edu

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A) is a multifunctional cytokine with important roles in pathological angiogenesis. Using an adenoviral vector engineered to express murine VEGF-A164, we previously investigated the steps and mechanisms by which this cytokine induced the formation of new blood vessels in adult immunodeficient mice and demonstrated that the newly formed blood vessels closely resembled those found in VEGF-A–expressing tumors. We now report that, in addition to inducing angiogenesis, VEGF-A164 also induces a strong lymphangiogenic response. This finding was unanticipated because lymphangiogenesis has been thought to be mediated by other members of the VPF/VEGF family, namely, VEGF-C and VEGF-D. The new "giant" lymphatics generated by VEGF-A164 were structurally and functionally abnormal: greatly enlarged with incompetent valves, sluggish flow, and delayed lymph clearance. They closely resembled the large lymphatics found in lymphangiomas/lymphatic malformations, perhaps implicating VEGF-A in the pathogenesis of these lesions. Whereas the angiogenic response was maintained only as long as VEGF-A was expressed, giant lymphatics, once formed, became VEGF-A independent and persisted indefinitely, long after VEGF-A expression ceased. These findings raise the possibility that similar, abnormal lymphatics develop in other pathologies in which VEGF-A is overexpressed, e.g., malignant tumors and chronic inflammation.

Key Words: VEGF-C • VEGF-D • PlGF • VPF/VEGF • VEGF-A


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