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Blood, 1 December 2000, Vol. 96, No. 12, pp. 3801-3808
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Ligation of CD40 induces the expression of vascular endothelial
growth factor by endothelial cells and monocytes and promotes
angiogenesis in vivo
Michael Melter,
Marlies E. J. Reinders,
Masayuki Sho,
Soumitro Pal,
Christopher Geehan,
Mark D. Denton,
Debabrata Mukhopadhyay, and
David M. Briscoe
From The Division of Nephrology, Department of
Medicine, Children's Hospital; the Department of Pediatrics, Harvard
Medical School; and the Department of Pathology, Beth Israel Deaconess
Medical Center, Boston, MA.
This study addresses a mechanism by which lymphocytes may promote
vascular endothelial growth factor (VEGF) expression and angiogenesis
in immune inflammation. Resting human umbilical endothelial cells (HUVECs) were found to express low levels of VEGF messenger RNA
(mRNA) by reverse transcription polymerase chain reaction and
ribonuclease protection assay with little or no change in expression
following activation by cytokines, including tumor necrosis factor- ,
interleukin (IL)-1, interferon  , or IL-4. In contrast, treatment of
HUVECs and monocytes with soluble CD40 ligand (sCD40L) resulted in a
marked dose-dependent induction of VEGF mRNA (approximately 4-fold),
which peaked between 1 and 5 hours post-stimulation. Transient
transfection of HUVECs was performed with a luciferase reporter
construct under the control of the human VEGF promoter. Treatment of
transfected HUVECs with sCD40L was found to enhance luciferase activity
(approximately 4-fold) compared with controls, similar to the relative
fold induction in mRNA expression in parallel cultures. Thus,
CD40-dependent VEGF expression was a result of transcriptional control
mechanisms. Treatment of HUVECs with sCD40L was also found to function
in vitro to promote growth and proliferation in a VEGF-dependent manner, and CD40-dependent HUVEC growth was comparable to that found
following treatment with recombinant human VEGF. Furthermore, subcutaneous injection of sCD40L in severe combined immunodeficient and
nude mice induced VEGF expression and marked angiogenesis in vivo.
Taken together, these findings are consistent with a function for
CD40L-CD40 interactions in VEGF-induced angiogenesis and define a
mechanistic link between the immune response and angiogenesis.
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