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5
1 Integrin, Induce Expression of CXC Chemokine-Dependent Angiogenic Activity1
*
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109
Monocyte-derived macrophages are important sources of angiogenic
factors in cancer and other disease states. Upon extravasation from
vasculature, monocytes encounter the extracellular matrix. We
hypothesized that interaction with extracellular matrix proteins leads
monocytes to adopt an angiogenic phenotype. We performed endothelial
cell chemotaxis assays on conditioned medium (CM) from monocytes that
had been cultured in vitro on various matrix substrates (collagen I,
laminin, Matrigel, fibronectin), in the presence of autologous serum,
or on tissue culture plastic alone. Monocytes cultured on Matrigel and
on fibronectin were the most potent inducers of angiogenic activity
compared with tissue culture plastic or autologous serum-differentiated
monocytes. This increased angiogenic activity was associated with
increased expression of angiogenic CXC chemokines (IL-8, epithelial
neutrophil-activating peptide-78, growth-related oncogene 
, and
growth-related oncogene 
) but not of vascular endothelial growth
factor. Additionally, CM from monocytes cultured on
fibronectin-depleted Matrigel (MGFN-) induced
significantly less angiogenic activity than CM from monocytes cultured
on control-depleted Matrigel. ELISA analysis of CM from monocytes
cultured on MGFN- revealed a significant decrease in
GRO- and GRO- compared with CM from monocytes cultured on MG.
Incubation of monocytes before adherence on fibronectin with PHSCN (a
competitive peptide inhibitor of the PHSRN sequence of fibronectin
binding via 5
1 integrin) results in
diminished expression of angiogenic activity and CXC chemokines
compared with control peptide. These data suggest that fibronectin, via
51 integrin, promotes CXC
chemokine-dependent angiogenic activity from
monocytes.
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