ACUTE REDUCTIONS IN BLOOD-FLOW AND SHEAR-STRESS INDUCE PLATELET-DERIVED GROWTH FACTOR-A EXPRESSION IN BABOON PROSTHETIC GRAFTS

Abrupt reductions in fluid shear stress induce subendothelial smooth m uscle cells (SMCs) to proliferate in exper- imental prosthetic grafts. Platelet-derived growth factor (PDGF), an important SMC mitogen, is e xpressed by cultured endothelial cells and modulated by shear stress. We hypothesized that this growth factor would be modulated by changes in shear stress in vivo. Bilateral aortoiliac prosthetic grafts were i mplanted into five baboons. High flow was generated by construction of femoral arteriovenous fistulas on both sides. Two months later, one o f the fistulas was ligated, reducing shear stress in the upstream graf t by 78+/-6%. Four days after fistula ligation, all grafts were remove d and analyzed. As previously reported. SMC proliferation in low-flow grafts exceeded that in high-flow grafts, although the neointimal area was similar. mRNA levels for PDGF-A were significantly increased in l ow-flow grafts compared with high-flow grafts. In situ hybridization a nd immunohistochemical studies localized the increased PDGF-A mRNA and protein to the luminal endothelium and subjacent SMCs. Abrupt reducti ons in blood flow and fluid shear stress may induce accelerated neoint imal thickening by a PDGF-A-mediated mechanism, since endothelial expr ession of this gene is temporally and anatomically associated with neo intimal SMC proliferation.