Expression of vascular endothelial growth factor and its receptors correlates closely with formation of the plexiform lesion in human pulmonary hypertension

The pulmonary vasculature exhibits various morphological changes in patient s with pulmonary hypertension (PH). Among them, the plexiform lesion is one of the most characteristic vascular lesions, although nothing is known abo ut the molecular mechanisms of its formation. In the present study, the exp ression of vascular endothelial growth factor (VEGF), an endothelial cell-s pecific angiogenic mitogen, and its receptors, fms-like tyrosine kinase (Fl t-1) and kinase insert domain-containing receptor (KDR), in the lungs of fi ve cases with PH, were examined. By in situ hybridization, VEGF expression was found in modified smooth muscle cells inside the plexiform lesions as w ell as in medial smooth muscle cells of the arteries adjacent to the lesion s. The expression of Flt-1 mRNA was observed in endothelial cells of the ar teries adjacent to the plexiform lesions, while KDR mRNA was expressed in t he endothelial cells inside the plexiform lesions. VEGF was immunolocalized to the endothelial cells expressing its receptors as well as the modified smooth muscle cells producing VEGF. These results demonstrate that VEGF and its receptors are upregulated with a close correlation to the plexiform le sions, and suggest that VEGF expressed by smooth muscle cells may activate the endothelial cells to form the plexiform lesions.