VEGF in the lung: a role for novel isoforms

Abstract

Vascular endothelial cell growth factor (VEGF) is a potent mitogen and permogen that increases in the plasma and decreases in the alveolar space in respiratory diseases such as acute respiratory distress syndrome (ARDS). This observation has led to controversy over the role of this potent molecule in lung physiology and disease. We hypothesized that some of the VEGF previously detected in normal lung may be of the anti-angiogenic family (VEGF_xxxb) with significant potential effects on VEGF bioactivity. VEGF_xxxb protein expression was assessed by indirect immunohistochemistry in normal and ARDS tissue. Expression of VEGF_xxxb was also detected by immunoblotting in normal lung tissue, primary human alveolar type II (ATII) cells, and bronchoalveolar lavage (BAL) fluid in normal subjects and by ELISA in normal, “at risk,” and ARDS subjects. The effect of VEGF₁₆₅ and VEGF₁₆₅b on both human primary endothelial cells and alveolar epithelial cell proliferation was assessed by [³H]thymidine uptake. We found that VEGF₁₆₅b was widely expressed in normal healthy lung tissue but is reduced in ARDS lung. VEGF₁₂₁b and VEGF₁₆₅b were present in whole lung, BAL, and ATII lysate. The proliferative effect of VEGF₁₆₅ on both human primary endothelial cells and human alveolar epithelial cells was significantly inhibited by VEGF₁₆₅b (P < 0.01). These data demonstrate that the novel VEGF_xxxb family members are expressed in normal lung and are reduced in ARDS. A specific functional effect on primary human endothelial and alveolar epithelial cells has also been shown. These data suggest that the VEGF_xxxb family may have a role in repair after lung injury.