The pulmonary vasculature exhibits various morphological changes in patients with pulmonary hypertension (PH). Among them, the plexiform lesion is one of the most characteristic vascular lesions, although nothing is known about the molecular mechanisms of its formation. In the present study, the expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific angiogenic mitogen, and its receptors, fms-like tyrosine kinase (Flt-1) and kinase insert domain-containing receptor (KDR), in the lungs of five cases with PH, were examined. By in situ hybridization, VEGF expression was found in modified smooth muscle cells inside the plexiform lesions as well as in medial smooth muscle cells of the arteries adjacent to the lesions. The expression of Flt-1 mRNA was observed in endothelial cells of the arteries adjacent to the plexiform lesions, while KDR mRNA was expressed in the 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 lesions, and suggest that VEGF expressed by smooth muscle cells may activate the endothelial cells to form the plexiform lesions.

Angiogenesis is an indispensable process in the chronic proliferative synovitis and pannus formation of rheumatoid arthritis (RA). This study examined the expression of vascular endothelial growth factor (VEGF) isoforms and VEGF receptors, Flt-1, KDR and neuropilin-1, in RA and osteoarthritis (OA) synovia, and studied the relationship between their expression and the synovial angiogenesis. By RT-PCR analysis, the isoform VEGF 121 was constitutively expressed in all the RA (17/17 patients) and OA (8/8 patients) synovia. In contrast, the expression of the isoform VEGF 165 was observed in 41% of the RA synovia (7/17 patients), but was undetectable in the OA samples (0/8 patients). The receptor Flt-1 was almost constitutively expressed in RA (15/17 patients) and OA (8/8 patients) synovia, while the expression of KDR was detected in the synovia of six RA patients (6/17 patients; 35%) but none of the OA patients (0/8 patients). The expression of neuropilin-1, an isoform-speci®c receptor for VEGF 165 which enhances the binding of VEGF 165 to KDR, was also up-regulated in the same RA synovia that expressed KDR. Furthermore, there was a close correlation between the expression of isoform VEGF 165 and that of its receptors KDR and neuropilin-1. Morphometric analysis demonstrated that the vascular density is signi®cantly higher in the RA synovial tissues with expression of VEGF 165 , KDR, and neuropilin-1 than in those without their expression ( p<0.01). In situ hybridization and immunohistochemical studies indicated that the cells expressing VEGF are macrophage-like synovial lining cells and spindle-shaped cells in the sublining cell layer. These results suggest that the selective up-regulation of the isoform VEGF 165 and its signalling via KDR and neuropilin-1 play an important role in the synovial angiogenesis which occurs in RA.

Angiogenesis is an indispensable process in the chronic proliferative synovitis and pannus formation of rheumatoid arthritis (RA). This study examined the expression of vascular endothelial growth factor (VEGF) isoforms and VEGF receptors, Flt-1, KDR and neuropilin-1, in RA and osteoarthritis (OA) synovia, and studied the relationship between their expression and the synovial angiogenesis. By RT-PCR analysis, the isoform VEGF(121) was constitutively expressed in all the RA (17/17 patients) and OA (8/8 patients) synovia. In contrast, the expression of the isoform VEGF(165) was observed in 41% of the RA synovia (7/17 patients), but was undetectable in the OA samples (0/8 patients). The receptor Flt-1 was almost constitutively expressed in RA (15/17 patients) and OA (8/8 patients) synovia, while the expression of KDR was detected in the synovia of six RA patients (6/17 patients; 35%) but none of the OA patients (0/8 patients). The expression of neuropilin-1, an isoform-specific receptor for VEGF(165) which enhances the binding of VEGF(165) to KDR, was also up-regulated in the same RA synovia that expressed KDR. Furthermore, there was a close correlation between the expression of isoform VEGF(165) and that of its receptors KDR and neuropilin-1. Morphometric analysis demonstrated that the vascular density is significantly higher in the RA synovial tissues with expression of VEGF(165), KDR, and neuropilin-1 than in those without their expression (p<0.01). In situ hybridization and immunohistochemical studies indicated that the cells expressing VEGF are macrophage-like synovial lining cells and spindle-shaped cells in the sublining cell layer. These results suggest that the selective up-regulation of the isoform VEGF(165) and its signalling via KDR and neuropilin-1 play an important role in the synovial angiogenesis which occurs in RA.

HOXB9 expression, which promotes tumor proliferation and angiogenesis, is a significant prognostic factor in breast cancer.

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