DIFFERENTIAL NITRIC-OXIDE PRODUCTION BY MICROVASCULAR AND MACROVASCULAR ENDOTHELIAL-CELLS

Phenotypic heterogeneity among endothelial cell populations may accoun t for important organ-specific behaviors. Experimental evidence sugges ts that endothelium-derived nitric oxide mediates certain of these uni que responses. The purpose of these investigations was to compare rat pulmonary microvascular endothelial cells with pulmonary artery and ao rtic macrovascular endothelial cells in their ability to generate nitr ic oxide (NO). Cultures of these microvascular and macrovascular endot helial cells were incubated with interferon-gamma (IFN-gamma), tumor n ecrosis factor-alpha (TNF-alpha), and Salmonella typhimurium lipopolys accharide (LPS) alone or in combination, and nitrite production was me asured. Single-agent exposure with IFN-gamma (up to 1,000 U/ml), TNF-a lpha (up to 60,000 U/ml), or LPS (up to 500 ng/ml) had little effect o n nitrite generation. Nitrite production by rat aortic macrovascular e ndothelial cells (RAEC) was significantly greater than that by the rat lung microvascular endothelial cells (RLMVEC) when stimulated with TN F-alpha + IFN-gamma, LPS + IFN-gamma, or TNF-alpha + LPS. The maximal response by all endothelial cell types (similar to 15-fold increase in RAEC and 8-fold increase in RLMVEC) was observed with LPS + IFN-gamma . The nitrite generation from rat pulmonary artery endothelial cells w as intermediate between RAEC and RLMVEC responses when stimulated with IFN-gamma + LPS or TNF-alpha. Similar patterns of heterogeneous induc ible nitric oxide synthase mRNA induction occurred when Northern analy sis of specimens from the cultured endothelial cell types was done. Th ese data suggest that phenotypic heterogeneity between these endotheli al cell populations is substantial and, by inference, that site-specif ic NO . generation may occur.