Abstract
The maintenance of endothelial cell-cell junctions is vital for the control of blood vessel leakage and is known to be important in the growth and maturation of new blood vessels during angiogenesis. Here we have investigated the role of a tight junction molecule, Claudin14, in tumour blood vessel leakage, angiogenesis and tumour growth. Using syngeneic tumour models our results showed that genetic ablation of Claudin14 was not sufficient to affect tumour blood vessel morphology or function. However, and surprisingly, Claudin14-heterozygous mice displayed several blood vessel-related phenotypes including: disruption of ZO-1-positive cell-cell junctions in tumour blood vessels; abnormal distribution of basement membrane laminin around tumour blood vessels; increased intratumoural leakage and decreased intratumoural hypoxia. Additionally, although total numbers of tumour blood vessels were increased in Claudin14-heterozygous mice, and in VEGF-stimulated angiogenesis ex vivo, the number of lumenated vessels was not changed between genotypes and this correlated with no difference in syngeneic tumour growth between wild-type, Claudin14-heterozygous and Claudin14-null mice. Lastly, Claudin14-heterozygosity, but not complete deficiency, also enhanced endothelial cell proliferation significantly. These data establish a new role for Claudin14 in the regulation of tumour blood vessel integrity and angiogenesis that is evident only after the partial loss of this molecule in Claudin14-heterozyous mice but not in Claudin14-null mice.
Highlights
Blood vessel maturation, during angiogenesis, involves establishment of endothelial cell-cell contacts, deposition of an intact basement membrane, lumen formation and the recruitment of supporting cells [1,2,3]
No effects on Mendelian ratios or male:female ratios were observed in litters (Figure S1 A–C). qPCR analysis confirmed that levels in Cldn14-het organs were approximately half those detected in WT mice, whilst Cldn14 transcript was undetectable in Cldn14-nulls (Figure S1 D)
Given that Cldn14 is a tight junction protein, we first asked whether deletion of Cldn14 could affect tumour endothelial cellcell junction organisation
Summary
Blood vessel maturation, during angiogenesis, involves establishment of endothelial cell-cell contacts, deposition of an intact basement membrane, lumen formation and the recruitment of supporting cells [1,2,3]. The quality of tumour blood vessels differs significantly from the normal vasculature. Their rapid formation leads to increased vessel leakage, poorly controlled lumen formation and discontinuous supporting cell association. Endothelial cell-cell junction integrity is a determinant of vascular permeability. Tight junctions (TJs) in both epithelial and endothelial cells consist of several protein families, including JAMs, occludin and claudins [6]. The regulation of TJ formation [8], [9] can impact upon several cellular processes, including vascular permeability and cell proliferation [10], [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
