LIF transduces contradictory signals on capillary outgrowth through induction of Stat3 and (P41/43)MAP kinase

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.