Cooperation between low density lipoproteins and IGF-I in the promotion of mitogenesis in vascular smooth muscle cells

Low density lipoproteins (LDL) are an independent risk factor for atherosclerosis and show synergism with some growth factors in vascular smooth muscle cell (VSMC) proliferation. lGF-I has mitogenic actions on VSMC, which, in turn, show enhanced expression of IGF-l and its receptor when exposed to hypercholesterolemic diets in vivo. To investigate the molecular basis of a possible interaction between LDL and the IGF-I signaling system in VSMC, we used A10 cells, where synergism between both factors in DNA synthesis was demonstrated. IGF-I activates phosphatidylinositol 3-kinase (P13 kinase) and extracellular signal-regulated MAPK pathways in A10 cells, although insulin receptor substrate-1 (IRS-1)-associated P13 kinase is more closely linked to IGF-I induced proliferation. LDL, in pathophysiological concentrations, affect the IGF-l signaling pathway at multiple levels: 1) they induce phosphorylation of IGF-I receptor beta and IRS-1 in a time- and dose-dependent manner; 2) they up-regulate IRS-1-associated P13 kinase/Akt activation in response to lGF-1 at early times; and 3) they show additive effects with IGF-I on extracellular signal-regulated MAPK 1/2 phosphorylation. These actions are not present in very low density lipoprotein treatments. Taken together, these results indicate specific cooperation between LDL and the IGF-I signaling pathways and may represent a more general mechanism through which proatherogenic lipoproteins modulate VSMC response to growth factors.