Smooth muscle cell proliferation induced by oxidized LDL-borne lysophosphatidylcholine: Evidence for FGF-2 release from cells not extracellular matrix

Oxidized low-density lipoprotein (oxLDL), which accumulates in vascular lesions, alters vascular cell function in ways that can be construed as atherogenic. Among these is the observation that oxLDL and its lipids promote smooth muscle cell (SMC) proliferation. A number of schemes have been proposed to explain this phenomenon. Our published data support the concept that part of the proliferation is mediated by lysophosphatidylcholine (lysoPC) and structurally related phospholipids borne by oxLDL, which cause FGF-2 release via an oxidant-dependent mechanism. Since FGF-2 can bind extracellular matrices, we wanted to determine whether the FGF-2 released came from an intracellular or an extracellular matrix-bound pool. We tested whether lysoPC was capable of releasing FGF-2 from SMC matrices, whether agents that release FGF-2 from matrices could cause proliferation, and whether lysoPC-mediated proliferation could occur by stimulating metalloproteinase (MMP)-induced matrix degradation, which released matrix-bound FGF-2. Our results indicate that the source of FGF-2 released by lysoPC and related lipids is a preexisting cellular pool and not from matrix, and that the mechanism likely involves transient, sublethal cell permeabilization. These results enhance understanding of a mechanism by which oxLDL could contribute to SMC proliferation in arterial lesions.