HEPARIN AND THE PHENOTYPE OF ADULT HUMAN VASCULAR SMOOTH-MUSCLE CELLS

To study mechanisms controlling growth and phenotype in human vascular smooth muscle cells, we established culture conditions under which th ese cells proliferate rapidly and achieve Life-spans of 50-60 populati on doublings. In medium containing heparin and heparin-binding growth factors, growth rate and life-span of human vascular smooth muscle cel ls increased more than 50% relative to cultures with neither supplemen t, and more than 20% compared to cultures supplemented only with hepar in-binding growth factors. In contrast to observations made in rat vas cular smooth muscle cells, smooth muscle-specific alpha-actin in the h uman cells was expressed only in the presence of heparin and colocaliz ed with beta/gamma nonmuscle actins in stress fibers, not in adhesion plaques. Heparin, in the presence of heparin-binding growth factors, a lso caused more than 170% stimulation of tracer glucosamine incorporat ion into hyaluronic acid and a 7.5-fold increase in hyaluronic acid ac cumulation. In comparison, total sulfate incorporation into sulfated g lycosaminoglycans increased by less than 40%. In light of our previous findings that heparin suppresses collagen gene expression, we conclud e that heparin induces human vascular smooth muscle cells exposed to h eparin-binding growth factors to remodel their extracellular matrix by altering the relative rates of hyaluronic acid (HA) and collagen synt hesis. The resulting hyaluronic-acid-rich, collagen-poor matrix may en hance infiltration of CD44/hyaluronate-receptor-bearing T-lymphocytes and monocytes into the vascular wall, an early event in atherogenesis.