H. Paradis et Rl. Gendron, LIF transduces contradictory signals on capillary outgrowth through induction of Stat3 and (P41/43)MAP kinase, J CELL SCI, 113(23), 2000, pp. 4331-4339
The signaling pathways regulating blood vessel growth and development are n
ot well understood. In the present report, an in vitro model was used to id
entify signaling pathways regulating capillary formation in embryonic endot
helial cells, Basic fibroblast growth factor (bFGF) plus leukemia inhibitor
y factor (LIF) optimally stimulate the formation of capillary-like structur
es of the embryonic endothelial cell line IEM. LIF stimulation of IEM cells
leads to activation of the Stat3 as well as the (P41/43)mitogen-activated
protein kinase ((P41/43)MAPK) cascade, while bFGF does not activate Stat3 b
ut does induce the (P41/43)MAPK cascade. Inhibition of Stat3 DNA-binding ac
tivity by expression of a dominant inhibitory Stat3 mutant increases the ca
pillary outgrowth of the IEM cells induced by LIF, Increased Stat3 activity
by overexpression of the wild-type Stat3 greatly reduced capillary outgrow
th. In contrast, inhibition of the (P41/43)MAPK cascade using a MEK-1 inhib
itor,dramatically inhibits the LIF-induced capillary outgrowth. Moreover, t
he increased formation of capillary-like structures of the IEM cells mediat
ed by Stat3 inhibition does not overcome the requirement for activation of
the (P41/43)MAPK pathway for capillary outgrowth. Stat3 activity correlates
with the LIF-induced expression of the negative feedback regulators of the
Janus (JAK) family of tyrosine kinases, SOCS-1 and SOCS-3. These results p
rovide evidence that Stat3 acts as a negative regulator of capillary outgro
wth, possibly by increasing SOCS-1 or SOCS-3 expression. The contradictory
signals stimulated by LIF could be necessary to control the intensity of th
e response leading to capillary outgrowth in vivo.