L-arginine is metabolized to nitric oxide (NO) by NO synthase (NOS) or to urea and L-ornithine by arginase. L-ornithine contributes to vascular remodeling in pulmonary hypertension via metabolism to polyamines and proline. Previously we found that cytokines upregulate both NOS and arginase in PAEC. We hypothesized that cytokine-induced arginase I and II expression depend on epidermal growth factor receptor (EGFR) activity. bPAEC were treated with lipopolysaccharide and tumor necrosis factor-a (L/T). L/T treatment resulted in a substantial increase in urea production, and this increase in urea production was potently inhibited by both genistein and AG1478, inhibitors of EGFR. Levels of arginase I protein and arginase II mRNA were increased in response to L/T treatment, and genistein prevented the L/T-induced elevations in both arginase I protein and arginase II mRNA levels. L/T treatment increased production of nitrites and iNOS mRNA accumulation, and genistein and AG1478 had little effect on these changes. Epidermal growth factor (EGF; 50 ng/ml) treatment resulted in enhanced urea production. Finally, a 170 kDa protein was phosphorylated upon treatment with either EGF or L/T. Our results indicate that arginase induction by L/T depends in part on EGFR activity. We speculate that EGFR inhibitors may attenuate vascular remodeling without affecting NO release, and thus may represent novel therapeutic modalities for pulmonary hypertensive disorders.