Non-triple helical form of type IV collagen alpha1 chain suppresses vascular endothelial-cadherin mediated cell-to-cell junctions

Non-triple helical collagen polypeptide alpha 1(IV) (NTH alpha 1(IV)) is a gene product of COL4A1 and is secreted as a polypeptide chain without the triple helix structure under physiological conditions. Studies have shown that NTH alpha 1(IV) is up-regulated in and around vascular endothelial cells during neovascularization and vascular-like networks of in vitro angiogenesis models, suggesting its involvement in angiogenesis. In the present study, we examined the effect of NTH alpha 1(IV) on endothelial cell-to-cell junctions, and we found that NTH alpha 1(IV) suppressed VE-cadherin (vascular endothelial cadherin) mediated junctions and promoted cellular migration in human umbilical vein endothelial cell cultures. NTH alpha 1(IV) is potentially a factor that induces VE-cadherin endocytosis and promotes neovascular sprouting and elongation. The possible mechanism entails endocytosis of NTH alpha 1(IV) by its cellular receptor(s), Endo180 and/or other proteins, which results in the clearance of the cellular receptor(s) from the cell surface, thus inducing the endocytosis of VE-cadherin. Because the NC1 domain of the a1 chain of type IV collagen, called arresten, is considered an endogenous inhibitor of angiogenesis, it seems that the single polypeptide chain of NTH alpha 1(IV) has conflicting functions.