TENASCIN-C, PROLIFERATION AND SUBENDOTHELIAL FIBRONECTIN IN PROGRESSIVE PULMONARY VASCULAR-DISEASE

Progressive pulmonary hypertension is characterized by smooth muscle c ell proliferation and migration leading to occlusive arterial lesions. Previously, using cultured smooth muscle cells, we demonstrated that epidermal growth factor (EGF)-dependent proliferation and migration ar e dependent on tenascin-C (Tn) and cellular fibronectin (Fn), respecti vely. In this study we applied immunohistochemistry to lung biopsy tis sue from patients with congenital heart defects and pulmonary hyperten sion to determine how the distribution and intensity of Tn, EGF, proli ferating cell nuclear antigen (PCNA), and Fn expression related to art erial abnormalities. With mildly increased wall thickness, minimal Tn, PCNA, and EGF was evident. With progressive hypertrophy, moderately i ntense foci of Tn were apparent in the adventitia, periendothelium, an d occasionally the media but not consistently co-distributing with EGF and PCNA. With obstructive lesions, intense neointimal Tn expression co-localized with EGF and PCNA. Fn accumulation in the periendothelium increased with medial hypertrophy and became more widespread in a dif fuse pattern with neointimal formation. The neointima was predominantl y composed alpha-smooth-muscle-actin-positive cells, occasional inflam matory cells with no evidence of apoptosis. These studies are consiste nt with Tn modulating EGF-dependent neointimal smooth muscle cell prol iferation and Fn providing a gradient for smooth muscle cell migration from media to neointima.