Hypoxia-inducible factor 1 (HIF-1) activates transcription of
genes encoding angiogenic growth factors, which are secreted by
hypoxic cells and stimulate endothelial cells, leading to angiogenesis.
To determine whether HIF-1 also mediates cell-autonomous responses
to hypoxia, we have compared gene expression profiles in arterial
endothelial cells cultured under nonhypoxic versus hypoxic conditions
and in nonhypoxic cells infected with adenovirus encoding beta-galactosidase
versus a constitutively active form of HIF-1alpha (AdCA5). There
were 245 gene probes that showed at least 1.5-fold increase in
expression in response to hypoxia and in response to AdCA5; 325
gene probes showed at least 1.5-fold decrease in expression in
response to hypoxia and in response to AdCA5. The largest category
of genes down-regulated by both hypoxia and AdCA5 encoded proteins
involved in cell growth/proliferation. Many genes up-regulated
by both hypoxia and AdCA5 encoded cytokines/growth factors, receptors,
and other signaling proteins. Transcription factors accounted
for the largest group of HIF-1-regulated genes, indicating that
HIF-1 controls a network of transcriptional responses to hypoxia
in endothelial cells. Infection of endothelial cells with AdCA5
under nonhypoxic conditions was sufficient to induce increased
basement membrane invasion and tube formation similar to the responses
induced by hypoxia, indicating that HIF-1 mediates cell-autonomous
activation of endothelial cells.