Relationship of molecular structure to the mechanism of lysophospholipid-induced smooth muscle cell proliferation

We previously reported that oxidized low-density lipoprotein and one of its constituents, lysophosphatidylcholine (lysoPC), caused smooth muscle cell proliferation that was inhibitable by vitamin E and by a neutralizing antib ody against basic fibroblast growth factor-2 (FGF-2). We now show that the mitogenic activity of lysolipids is highly dependent on structure. Phosphol ipids with palmitoyl fatty acid and phosphocholine induced DNA synthesis op timally. Shorter and longer fatty acids were significantly less potent, as were phosphoserine and phosphoethanolamine head groups. Structurally relate d phospholipids [platelet-activating factor (PAF) and lysoPAF] were also mi togens and acted via an analogous FGF-2-dependent, vitamin E-inhibitable me chanism. The mechanism of lysoPC stimulation was distinct from that of anot her phospholipid mitogen, lysophosphatidic acid (lysoPA), in that lysoPC st imulation was not pertussis toxin inhibitable. Furthermore, lysoPA stimulat ion was not inhibitable by vitamin E. Despite its distinct cellular pathway for stimulation, lysoPA also ultimately led to FGF-2 release. Our data sho w that specific structural attributes of lysoPC, PAF, and lysoPAF enable th ese agents to mediate smooth muscle cell release of FGF-2, which in turn st imulates proliferation.