VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION IN TRANSPLANTED HUMAN HEARTS

Vascular endothelial growth factor (VEGF) is an endothelial cell-speci fic mitogen thought to play an important role in coronary collateral v essel formation, We used immunocytochemistry to determine VEGF express ion in biopsies (n=283) of transplanted human hearts (n=109) with and without microvascular fibrin, Measures of vascular fibrin, alpha, plas min-inhibitor (a,Pl), macrophages, neutrophils, and serum cardiac trop onin T titers were used to evaluate myocardial damage. Antibody to T l ymphocytes was used to evaluate cellular rejection, and HLA-DR, ICAM-1 , and PAL-E antibodies were used to assess endothelial cell activation and phenotypic changes in the microcirculation. No VEGF immunoreactiv ity was detected in control donor hearts without fibrin, but the propo rtion of biopsies demonstrating VEGF immunoreactivity increased signif icantly in allografts with increasing fibrin and a(2)PI reactivity (P= 0.0001), VEGF immunoreactivity was confined to areas of fibrin deposit ion and was associated with infiltrates of macrophages and neutrophils (P<0.0001), but not with T cells (P=0.10), Biopsies with fibrin/VEGF reactivity were associated with increased capillary endothelial cell H LA-DR, ICAM-1, and PAL-E reactivity, In a subset of patients, serum ca rdiac troponin-T values were greater in patients with VEGF-positive (n =21) than VEGF-negative (n=19) biopsies (P=0.05), Nested RT-PCR demons trated that biopsies with and without fibrin-NEGF immunoreactivities e xpressed VEGF(121), VEGF and VEGF(189) variants, with VEGF(165) being 165, the dominate variant, These results indicate that endogenous VEGF is expressed locally following vascular thrombosis and myocardial cel l damage, and that VEGF expression may be related to endothelial cell activation and phenotypic changes found in the microcirculation of car diac allografts.