Abstract 1630: LAR Modulates Insulin-like Growth Factor-1-induced Endothelial Cell Signals for Growth, Migration and Tube Formation
Insulin-like growth factor-1 (IGF-1) induces endothelial cell migration and promotes angiogenesis. We showed previously that leukocyte antigen-related (LAR) protein tyrosine phosphatase is a negative regulator of IGF-1-induced signaling in vascular smooth muscle cells. Here, we investigated the effect of LAR expression on IGF-1-induced signaling in human umbilical vein endothelial cells (HUVEC) and on endothelial tube formation. Adenovirus-mediated overexpression of LAR in HUVEC significantly inhibited IGF-1-induced phosphorylation of its receptor, IGF-1R. IGF-1 treatment increased phosphorylation of insulin receptor substrate-1 (IRS-1) and the association of IRS-1 with p85α subunit of phosphatidyl inositol 3-kinase (PI3K) in HUVEC and LAR overexpression inhibited these IGF-1-induced effects. Consistent with this, IGF-1-induced Akt phosphorylation was also significantly inhibited by LAR overexpression. Phosphorylation of endothelial nitric oxide synthase, a downstream effector of PI3K-Akt pathway, was enhanced in response to IGF-1 treatment in HUVEC and LAR overexpression abrogated IGF-1-induced eNOS phosphorylation. IGF-1-induced phosphorylation of extracellular-signal regulated kinases also decreased significantly in HUVEC overexpressing LAR. Overexpression of LAR impaired the inhibitory effect of IGF-1 on TNFα-induced apoptosis in HUVEC, but did not impair the inhibitory effect of VEGF on TNFα-induced apoptosis. Consistent with this, LAR overexpression also decreased the inhibitory effect of IGF-1 on TNFα-induced caspase-3 cleavage, caspage-3 activity, and DNA degradation. Moreover, IGF-1-stimulated HUVEC proliferation and migration were inhibited by the overexpression of LAR. In an in vitro angiogenesis assay, overexpression of LAR decreased IGF-1-mediated tube formation. In contrast, LAR overexpression had no significant effect on either HUVEC migration or tube formation induced by VEGF. Together, these data indicate that LAR specifically modulates divergent signaling pathways induced by IGF-1 and the expression of this PTP in vascular wall cells regulates cell survival and angiogenesis in pathophysiological conditions.