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Evaluation of the role of ANGPTL4 in tendon vascularization

University of British Columbia

The mechanisms that regulate angiogenic activity in injured or mechanically loaded tendons are poorly understood. In this study we hypothesised that repetitive stretching of tendon cells alters the expression and release of angiogenic factors which may promote tendon vascularization. In order to examine the effects of repetitive stretching on the expression of angiogenic genes, primary human tendon cells were subjected to cyclic stretching. Cyclic stretching of two-dimensional primary tenocyte cell cultures increased the expression of VEGF, bFGF and Cox-2. But, by extending the time course, VEGF, bFGF and Cox-2 were progressively downregulated. Angiogenic profiling of tendon cells by qPCR array identified a number of other genes (ANGPTL4, FGF-1, TGFα, VEGF-C and SPHK1) that responded to tensile loading in a similar pattern. Further experiments revealed that cyclic stretching of human tendon fibroblasts stimulated the expression and release of ANGPTL4 protein via TGF-β and HIF-1α signalling. ANGPTL4 promoted the angiogenic activity of endothelial cells. Angiogenic activity was also increased following injury and following ANGPTL4 injection into mouse patellar tendons, whereas the patellar tendons of ANGPTL4 knock out mice displayed reduced angiogenesis following injury. In human rotator cuff tendons, there were both spatial and quantitative associations of ANGPTL4 with tendon endothelial cells. The experiments described in this thesis have shown that ANGPTL4 may assist in the regulation of vascularity in injured or mechanically loaded tendon. TGF-β and HIF-1α are two signalling pathways that modulate the expression of ANGPTL4 by tendon fibroblasts and which could, in future, be manipulated to influence tendon healing or adaptation.

Text

2015-12-03

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/55672

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/