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 (VEGFxxxb) with significant potential effects on VEGF bioactivity. VEGFxxxb protein expression was assessed by indirect immunohistochemistry in normal and ARDS tissue. Expression of VEGFxxxb 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 VEGFxxxb 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 VEGFxxxb family may have a role in repair after lung injury.

Vascular Endothelial Growth Factor in Acute Lung Injury and Acute Respiratory Distress Syndrome

“…In vitro experiments have indicated that VEGF 165 b inhibits the proliferative effect of recombinant VEGF 165 protein on both human primary ECs and AE2 cells [126]. Taken together, these results also suggest a possible protective role for the VEGF xxx b family in fibroproliferation/repair after lung injury.…”

“…VEGF 165 induces the proliferation of AE2 cells in culture, an effect that can be inhibited by VEGF 165 b [126], thus factors that alter VEGF gene splicing may affect the fibroproliferative response in ARDS. The effect of VEGF on AE2 proliferation is discussed further in the section: ‘VEGF in Resolution/Repair from ARDS'.…”

“…Using animal models of pulmonary fibrosis, VEGFR2 inhibition attenuated pulmonary collagen deposition and TGF-β 1 signalling [127], whilst anti-VEGF therapy in the form of sFlt-1 resulted in a reduction in lung collagen deposition with additional anti-inflammatory and anti-angiogenic effects [128]. In contrast, targeted myeloid cell-specific deletion of VEGF aggravated bleomycin-induced pulmonary fibrosis [125], whilst mice with EC-specific VEGF deletion developed de novo pulmonary fibrosis that preceded multi-organ failure from systemic vascular pathologies [126]. …”

“…The presence of VEGF 165 b has also been demonstrated in healthy human lung tissue, with reduced levels of pulmonary expression reported in ARDS [126]. In vitro experiments have indicated that VEGF 165 b inhibits the proliferative effect of recombinant VEGF 165 protein on both human primary ECs and AE2 cells [126].…”

Advances in Understanding of the Pathogenesis of Acute Respiratory Distress Syndrome

“…This also appears to be anti-angiogenic and merits exploration. Further work is needed to establish the roles of these isoforms, which could be fruitful areas for therapies, but have yet to be explored in any detail outside oncological studies [49]. …”