Abstract
BackgroundAngiogenesis, the formation of new blood vessels from pre-existing vasculature is essential in a number of physiological processes such as embryonic development, wound healing as well as pathological conditions like, tumor growth and metastasis. Hyaluronic acid (HA), a high molecular weight polysaccharide, major component of extracellular matrix is known to associate with malignant phenotypes in melanomas and various other carcinomas. Hyaluronic acid binding protein 1 (HABP1) has been previously reported to trigger enhanced cellular proliferation in human liver cancer cells upon its over-expression. In the present study, we have identified the HA mediated cellular behaviour of liver endothelial cells during angiogenesis.MethodsEndothelial cells have been isolated from perfused liver of mice. Cell proliferation was studied using microwell plates with tetrazole dye. Cell migration was evaluated by measuring endothelial monolayer wound repair as well as through transwell migration assay. Alterations in proteins and mRNA expression were estimated by immunobloting and quantitative real time PCR using Applied Biosystems. The paraformaldehyde fixed endothelial cells were used for immuno- florescence staining and F-actin detection with conjugated antibodies. The images were captured by using Olympus florescence microscope (IX71).ResultsWe observed that administration of HA enhanced cell proliferation, adhesion, tubular sprout formation as well as migration of liver endothelial cells (ECs). The effect of HA in the rearrangement of the actins confirmed HA -mediated cytoskeleton re-organization and cell migration. Further, we confirmed enhanced expression of angiogenic factors like VEGF-A and VEGFR1 in endothelial cells upon HA treatment. HA supplementation led to elevated expression of HABP1 in murine endothelial cells. It was interesting to note that, although protein levels of β- catenin remained unaltered, but translocation of this protein from membrane to nucleus was observed upon HA treatment, suggesting its role not only in vessel formation but also its involvement in angiogenesis signalling.ConclusionsThe elucidation of molecular mechanism (s) responsible for HA mediated regulation of endothelial cells and angiogenesis contributes not only to our understanding the mechanism of disease progression but also offer new avenues for therapeutic intervention.
Highlights
Angiogenesis, the formation of new blood vessels from pre-existing vasculature is essential in a number of physiological processes such as embryonic development, wound healing as well as pathological conditions like, tumor growth and metastasis
We have demonstrated for the first time, that Plasmodium falciparum infected RBCs use Hyaluronic acid binding protein 1 (HABP1) as a receptor to bind to human endothelial cells [9]
Exogenous Hyaluronic acid (HA) treatment induces proliferation of endothelial cells Within the liver, HA is mostly synthesized by the sinusoidal pericytes, the hepatic stellate cells (HSCs) [24, 25] and removed from circulation through degradation especially by liver sinusoidal endothelial cells (LSEC) [26, 27]
Summary
Angiogenesis, the formation of new blood vessels from pre-existing vasculature is essential in a number of physiological processes such as embryonic development, wound healing as well as pathological conditions like, tumor growth and metastasis. Hyaluronic acid binding protein 1 (HABP1) has been previously reported to trigger enhanced cellular proliferation in human liver cancer cells upon its over-expression. The metastatic spread of tumor cells is the most lethal aspect of cancer, which often occurs through enhanced vascularization. The initiation of angiogenesis embarks with the local release of pro- and anti-angiogenic growth factors by endothelial cells (ECs). Such release occurs in response to disease- or injury- induced inflammation. A series of sequential events are involved in angiogenesis including local degradation of endothelial basement membrane by the action of proteases, formation of a lumen, proliferation and migration of endothelial cells that gives rise to a functional vessel
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