Nitric oxide modulates basal and endothelin-induced coronary artery vascular smooth muscle cell proliferation and collagen levels

The mechanisms governing the pathological accumulation of collagen in the extracellular matrix following angioplasty are complex, but may involve interactions between endothelium-derived paracrine agents and vascular cellular components. We tested the hypothesis that nitric oxide (NO) directly decreases collagen levels and decreases endothelin (ET-l)-stimulated increases in levels of specific collagen subtypes in coronary vascular smooth muscle cells (VSMC). Cultured VSMC were incubated for 48 h with the NO donor CAS 754 (10(-4) M), ET-1 (10(-8) M), or ET-1 plus CAS 754. In some experiments, angiotensin II (Ang II; 10(-8) M) was utilized in place of ET-1. Soluble collagen types I and III were quantitated with an ELISA method, and cell counts were performed, CAS 754 significantly inhibited cell proliferation (-17 +/- 2% upsilon control), basal total protein synthesis (-65 +/- 7% upsilon control), and basal collagen type I levels (-39 +/- 6% upsilon control), but not collagen type IIE levels. ET-1 and Ang II both significantly stimulated cell proliferation (26 +/- 5% upsilon control), total protein synthesis (169 +/- 6% upsilon control), and collagen type I levels (200 +/- 11% upsilon control). Ang II, but not ET-I, significantly increased collagen type III levels. Go-incubations of ET-I and GAS 754 resulted in a significant decrease in cell proliferation protein synthesis, and collagen levels (-23 +/- 2% upsilon control, 90 +/- 5% upsilon control, and 63 +/- 3% upsilon control, respectively) compared to ET-I alone. In contrast, co-incubation of Ang II and CAS 754 had no significant effect on cell proliferation, protein synthesis, and collagen levels seen with Ang II alone. These results demonstrate that NO inhibits basal collagen levels and cell division. Additionally, NO alters ET-1 stimulation of VSMC proliferation, protein synthesis, and production of extracellular matrix components. Thus, an imbalance in key endothelium-derived compounds could significantly impact upon extracellular matrix deposition following mechanical revascularization. (C) 1997 Academic Press Limited.