A 340 kDa hyaluronic acid secreted by human vascular smooth muscle cells regulates their proliferation and migration

The formation of atherosclerotic lesions is characterized by invasion ofvascular smooth muscle cells (VSMC) into the tunica intima of the arterialwall and subsequently by increased proliferation of VSMC, a processapparently restricted to the intimal layer of blood vessels. Both eventsare preceded by the pathological overexpression of several growth factors,such as platelet-derived growth factor (PDGF) which is a potent mitogen forVSMC and can induce their chemotaxis. PDGF is generally not expressed inthe normal artery but it is upregulated in atherosclerotic lesions. We havepreviously shown that PDGF-BB specifically stimulates proliferating VSMC tosecrete a 340 kDa hyaluronic acid (HA-340). Here, we present evidenceregarding the biological functions of this glycan. We observed that HA-340inhibited the PDGF-induced proliferation of human VSMC in a dose-dependentmanner and enhanced the PDGF-dependent invasion of VSMC through a basementmembrane barrier. These effects were abolished following treatment ofHA-340 with hyaluronidase. The effect of HA-340 on the PDGF-dependentinvasion of VSMC coincided with increased secretion of the 72-kDa type IVcollagenase by VSMC and was completely blocked by GM6001, a hydroxamic acidinhibitor of matrix metalloproteinases. HA-340 did not exert anychemotactic potency, nor did it affect chemotaxis of VSMC along a PDGFgradient. In human atheromatic aortas, we found that HA- 340 is expressedwith a negative concentration gradient from the tunica media to the tunicaintima and the atheromatic plaque. Our findings suggest that HA-340 may belinked to the pathogenesis of atherosclerosis, by modulating VSMCproliferation and invasion.