Background and Purpose-Arterial bifurcation apices are common sites for cerebral aneurysms, raising the possibility that the unique hemodynamic conditions associated with flow dividers predispose the apical vessel wall to aneurysm formation. This study sought to identify the specific hemodynamic insults that lead to maladaptive vascular remodeling associated with aneurysm development and to identify early remodeling events at the tissue and cellular levels. Methods-We surgically created new branch points in the carotid vasculature of 6 female adult dogs. In vivo angiographic imaging and computational fluid dynamics simulations revealed the detailed hemodynamic microenvironment for each bifurcation, which were then spatially correlated with histologic features showing specific tissue responses. Results-We observed 2 distinct patterns of vessel wall remodeling: (1) hyperplasia that formed an intimal pad at the bifurcation apex and (2) destructive remodeling in the adjacent region of flow acceleration that resembled the initiation of an intracranial aneurysm, characterized by disruption of the internal elastic lamina, loss of medial smooth muscle cells, reduced proliferation of smooth muscle cells, and loss of fibronectin. Conclusions-Strong localization of aneurysm-type remodeling to the region of accelerating flow suggests that a combination of high wall shear stress and a high gradient in wall shear stress represents a "dangerous" hemodynamic condition that predisposes the apical vessel wall to aneurysm formation.
We engineered implantable small-diameter blood vessels based on ovine smooth muscle and endothelial cells embedded in fibrin gels. Cylindrical tissue constructs remodeled the fibrin matrix and exhibited considerable reactivity in response to receptor-and nonreceptor-mediated vasoconstrictors and dilators. Aprotinin, a protease inhibitor of fibrinolysis, was added at varying concentrations and affected the development and functionality of tissue-engineered blood vessels (TEVs) in a concentration-dependent manner. Interestingly, at moderate concentrations, aprotinin increased mechanical strength but decreased vascular reactivity, indicating a possible relationship between matrix degradation/remodeling, vasoreactivity, and mechanical properties. TEVs developed considerable mechanical strength to withstand interpositional implantation in jugular veins of lambs. Implanted TEVs integrated well with the native vessel and demonstrated patency and similar blood flow rates as the native vessels. At 15 wk postimplantation, TEVs exhibited remarkable matrix remodeling with production of collagen and elastin fibers and orientation of smooth muscle cells perpendicular to the direction of blood flow. Implanted vessels gained significant mechanical strength and reactivity that were comparable to those of native veins. Our work demonstrates that fibrin-based TEVs hold significant promise for treatment of vascular disease and as a biological model for studying vascular development and pathophysiology. matrix degradation/remodeling; vascular disease; vascular reactivity; vascular tissue engineering; smooth muscle; endothelial cells MANY APPROACHES HAVE BEEN taken to replace diseased or damaged blood vessels. Synthetic conduits of polytetra-flouroethylene (Teflon, ePTFE) or polyethylene terephthalate (Dacron) have been used extensively with a great degree of success in replacement of large-diameter (Ͼ6 mm) vessels (9). However, small-diameter synthetic grafts displayed high failure rates due to thrombus and plaque formation. Adsorption of proteins or endothelial cells to the luminal surface of the grafts decreased thrombogenicity but did not restore vasoreactivity and long-term patency (8,9,11,26,37). Allogeneic grafts demonstrated long-term patency and reactivity, but their clinical use is prevented by high immunogenicity. Autografts, predominantly from saphenous veins or radial arteries, are the most widely used for small-diameter vessel replacement procedures such as coronary artery bypass. Although autologous grafts are currently the gold standard, limited availability, especially for repeat grafting procedures, and the pain and discomfort associated with the donor site necessitate the development of alternative technologies.Tissue engineering approaches that use natural or synthetic biomaterials as three-dimensional scaffolds for cell growth have been proposed. Natural biomaterials, derived from decellularized tissues, demonstrated successful infiltration of host cells and near physiological level of vasoreactivity after longte...
The large number of coronary artery bypass procedures necessitates development of off-the-shelf vascular grafts that do not require cell or tissue harvest from patients. However, immediate thrombus formation after implantation due to the absence of a healthy endothelium is very likely. Here we present the successful development of an Acellular Tissue Engineered Vessel (A-TEV) based on small intestinal submucosa that was functionalized sequentially with heparin and VEGF. A-TEVs were implanted into the carotid artery of an ovine model demonstrating high patency rates and significant host cell infiltration as early as one week post-implantation. At one month, a confluent and functional endothelium was present and the vascular wall showed significant infiltration of host smooth muscle cells exhibiting vascular contractility in response to vaso-agonists. After three months the endothelium aligned in the direction of flow and the medial layer comprised of circumferentially aligned smooth muscle cells. A-TEVs demonstrated high elastin and collagen content as well as impressive mechanical properties and vascular contractility comparable to native arteries. This is the first demonstration of successful endothelialization, remodeling, and development of vascular function of a cell-free vascular graft that was implanted in the arterial circulation of a pre-clinical animal model.
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