The human VE-cadherin promoter is subjected to organ-specific regulation and is activated in tumour angiogenesis

Abstract

Vascular endothelial (VE)-cadherin is exclusively expressed at interendothelial junctions of normal and tumour vessels. In this report, we characterized the transcriptional activity of the human VE-cadherin promoter. Transient transfection assays revealed that sequences at positions À1135/À744 and À166/À5 base pairs are critical for promoter activity in endothelial cells. We show that specific sequences in the proximal region interact with Ets and Sp1 family members. Transgenic mice were created and the human VE-cadherin promoter was able to confer correct temporal and spatial expression on the LacZ gene in embryos. In adults, the transgene was specifically and strongly expressed in the lung, heart, ovary, spleen and kidney glomeruli, whereas expression was weak or absent in the vasculature of other organs, including the brain, thymus, liver and skeletal muscle. Neovessels in tumour grafts and Matrigel implants harboured strong stainings, indicating that promoter activity is enhanced in angiogenic situations. Furthermore, Matrigel and transfection assays showed that VE-cadherin promoter is subjected to bFGF induction. Transgene expression was also noticed in extravascular sites of the central nervous system, suggesting that silencer elements may be located elsewhere in the gene. These results are a first step towards addressing the organ-and tumour-specific regulation of the VE-cadherin gene.

Angiogenesis: The VE-Cadherin Switch

“…In this model, promoter activity was downregulated during Huber et al 2005 VE-cadherin gland regression and restored after its regeneration. Increased promoter activity was also observed in mouse tumors and in VE-cadherin Matrigel plugs impregnated with bFGF ( ), suggesting that this cytokine might be the angiogenic factor responsible of Prandini et al 2005 transcription enhancement.…”

Cell-Cell Interactions and Cross Talk Described in Normal and Disease Conditions: Morphological Approach

“…Indeed, the expression of VE-cadherin is enhanced in activated, cancer-associated vessels, suggesting a causal involvement in tumor angiogenesis [35].…”

Non-invasive in vivo optical imaging of the lacZ and luc gene expression in mice

“…21 These b-Gal transgenic mice (n ¼ 14) received an intracardiac injection of DDAOG and were imaged 60 min later. As shown in Figure 4, the whole body of the transgenic mice were much fluorescent than the control mice (Figures 4a and b).…”

“…Imaging of the exposed organs after killing confirmed the presence of b-Gal in the lung, testis, kidney and guts, as described previously. 21 A quantitative comparison of b-Gal levels measured with NIR imaging or using a standardized enzymatic evaluation in vivo revealed how strongly optical properties of the organs were affecting the linearity of the CCD detection. When 'clear' organs were used, a good correlation was observed between the fluorescence measurement and the in vitro b-Gal assay.…”

“…VEcad-lacZ transgenic mice 21 and CD1 control mice (Charles River, l'Arbresle, France) were anesthetized and shaved with small animal clippers. b-Gal activity imaging was performed with 100-500 ms exposure times, before the substrate injection and every 10 s from the injection to 18 min after injection and then at 30 and 60 min after injection.…”