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 of vascular smooth muscle cells (VSMC) into the tunica intima of the a rterial wall and subsequently by increased proliferation of VSMC, a pr ocess apparently restricted to the intimal laver of blood vessels. Bot h events are preceded by the pathological overexpression of several gr owth factors, such as platelet-derived growth factor (PDGF) which is a potent mitogen for VSMC and can induce their chemotaxis. PDGF is gene rally not expressed in the normal artery but it is upregulated in athe rosclerotic lesions. We have previously shown that PDGF-BB specificall y stimulates proliferating VSMC to secrete a 340 kDa hyaluronic acid ( HA-340), Here, we present evidence regarding the biological functions of this glycan, me observed that HA-340 inhibited the PDGF-induced pro liferation of human VSMC in a dose-dependent manner and enhanced the P DGF-dependent invasion of VSMC through a basement membrane barrier. Th ese effects were abolished following treatment of HA-340 with hyaluron idase. The effect of HA-340 on the PDGF-dependent invasion of VSMC coi ncided with increased secretion of the 72-kDa type IV collagenase by V SMC and was completely blocked by GM6001, a hydroxamic acid inhibitor of matrix metalloproteinases. HA-340 did not exert any chemotactic pot ency, nor did it affect chemotaxis of VSMC along a PDGF gradient. In h uman atheromatic aortas, we found that HA-340 is expressed with a nega tive concentration gradient from the tunica media to the tunica intima and the atheromatic plaque. Our findings suggest that HA-340 may be l inked to the pathogenesis of atherosclerosis, by modulating VSMC proli feration and invasion.