Heart valve and blood vessel replacement using artificial prostheses is an effective strategy for the treatment of cardiovascular disease at terminal stage.Natural extracellular matrix(ECM)-derived materials(decellularized allogeneic or xenogenic tissues)have received extensive attention as the cardiovascular scaffold.However,the bioprosthetic grafts usually far less durable and undergo calcification and progressive structural deterioration.Glutaraldehyde(GA)is a commonly used crosslinking agent for improving biocompatibility and durability of the natural scaffold materials.However,the nature ECM and GA-crosslinked materials may result in calcification and eventually lead to the transplant failure.Therefore,studies have been conducted to explore new crosslinking agents.In this review,we mainly focused on research progress of ECM-derived cardiovascular scaffolds and their crosslinking strategies.
Objective： Procyanidins （PC） are widely available natural polyphenols. The present study is designed to investigate if PC can inhibit angiogenesis in lung adenocarcinoma xenografts through crosslinking vascular extracellular matrix （ECM） and preventing proteolysis by matrix metalloproteinases （MMPs）. Methods： Using the in vitro MMP-2 proteolysis and in vivo subcutaneous implantation models, we investigated if PC crosslinking inhibits MMP-mediated proteolysis. Using a cultured cell detachment assay, an in vitro angiogenesis assay, and a cell proliferation assay, we investigated if PC inhibits MMP-2-mediated endothelial cell detachment, angiogenesis, and cell proliferation, respectively. Using tumor xenografts, we evaluated if PC can inhibit growth of lung adenocarcinoma. Results： PC crosslink vascular ECM proteins, protecting them against proteolysis by MMPs in vitro and in vivo, protecting cultured human umbilical vein endothelial cells from detachment by MMP-2, and inhibiting in vitro angiogenesis. However, PC （0.75-100 μg/mL） did not inhibit vascular and tumor cells proliferation. PC injections （30 mg PC/kg bodyweight） in situ had anticancer effects on xenografts of lung adenocarcinoma, most likely by inhibiting angiogenesis during ECM proteolysis by MMPs. Conclusion： The results suggest that PC may be important MMP inhibitors that can be used as therapeutic anticancer agents.
