Background-Time-dependent activation of matrix metalloproteinases (MMPs) after myocardial infarction (MI) contributes to adverse left ventricular (LV) remodeling; however, noninvasive methods to monitor this process serially are needed. Methods and Results-MMP-targeted
The development of neotissue in tissue engineered vascular grafts remains poorly understood. Advances in mouse genetic models have been highly informative in the study of vascular biology, but have been inaccessible to vascular tissue engineers due to technical limitations on the use of mouse recipients. To this end, we have developed a method for constructing sub-1mm internal diameter (ID) biodegradable scaffolds utilizing a dual cylinder chamber molding system and a hybrid polyester sealant scaled for use in a mouse model. Scaffolds constructed from either polyglycolic acid or poly-l-lactic acid nonwoven felts demonstrated sufficient porosity, biomechanical profile, and biocompatibility to function as vascular grafts. The scaffolds implanted as either inferior vena cava or aortic interposition grafts in SCID/bg mice demonstrated excellent patency without evidence of thromboembolic complications or aneurysm formation. A foreign body immune response was observed with marked macrophage infiltration and giant cell formation by post-operative week 3. Organized vascular neotissue, consisting of endothelialization, medial generation, and collagen deposition, was evident within the internal lumen of the scaffolds by post-operative week 6. These results present the ability to create sub-1mm ID biodegradable tubular scaffolds that are functional as vascular grafts, and provide an experimental approach for the study of vascular tissue engineering using mouse models.
A dark band or rim along parts of the subendocardial border of the left ventricle (LV) and the myocardium has been noticed in some dynamic contrast-enhanced MR perfusion studies. The artifact is thought to be due to susceptibility effects from the gadolinium bolus, motion, or resolution, or a combination of these. Here motionless ex vivo hearts in which the cavity was filled with gadolinium are used to show that dark rim artifacts can be consistent with resolution effects alone. Magn Reson Med 54:1295-1299, 2005.
Matrix metalloproteinases (MMPs) are postulated to be necessary for neovascularization during wound healing. MMP-9 deletion alters remodeling postmyocardial infarction (post-MI), but whether and to what degree MMP-9 affects neovascularization post-MI is unknown. Neovascularization was evaluated in wild-type (WT; n ϭ 63) and MMP-9 null (n ϭ 55) mice at 7-days post-MI. Despite similar infarct sizes, MMP-9 deletion improved left ventricular function as evaluated by hemodynamic analysis. Blood vessel quantity and quality were evaluated by three independent studies. First, vessel density was increased in the infarct of MMP-9 null mice compared with WT, as quantified by Griffonia (Bandeiraea) simplicifolia lectin I (GSL-I) immunohistochemistry. Second, preexisting vessels, stained in vivo with FITClabeled GSL-I pre-MI, were present in the viable but not MI region. Third, a technetium-99m-labeled peptide (NC100692), which selectively binds to activated ␣v3-integrin in angiogenic vessels, was injected into post-MI mice. Relative NC100692 activity in myocardial segments with diminished perfusion (0 -40% nonischemic) was higher in MMP-9 null than in WT mice (383 Ϯ 162% vs. 250 Ϯ 118%, respectively; P ϭ 0.002). The unique finding of this study was that MMP-9 deletion stimulated, rather than impaired, neovascularization in remodeling myocardium. Thus targeted strategies to inhibit MMP-9 early post-MI will likely not impair the angiogenic response. leukocytes; remodeling; imaging REMODELING OF THE LEFT VENTRICLE (LV) postmyocardial infarction (post-MI) evokes changes to both cellular and extracellular matrix components to progressively alter LV structure and function (35). Matrix metalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases that can cleave all components of the extracellular matrix (ECM) and thereby exert influence on LV remodeling. MMPs are elevated after MI, and a cause and effect relationship between MMPs and LV remodeling has been demonstrated through the use of MMP inhibitors and MMP-null mice (23,38,55). In particular, MMP-9 is a 92-kDa gelatinase upregulated acutely post-MI, and MMP-9 gene deletion results in attenuated LV remodeling after MI (6, 22). Thus MMP-9 likely contributes to adverse LV remodeling post-MI.For the purposes of this study, we use neovascularization and angiogenesis interchangeably according to the following previously assigned definition: the sprouting of new vessels at the capillary level (48). MMPs have also demonstrated roles in neovascularization, and MMP inhibition has been postulated to inhibit the angiogenic process (43). Clinical trials with MMP inhibitors, however, have suggested that MMP inhibition may promote, rather than inhibit, neovascularization (2). MMP-9 is a specific MMP that has been implicated in angiogenesis, and the macrophage is one of several cell types that express MMP-9 post-MI (46). The exact role of MMPs, particularly MMP-9, in post-MI neovascularization is not clear. The MMP-9 substrate portfolio is broad and includes both angiogenic a...
the BEx technology and the research described herein. Z.V. and S.G.D. developed the surgical procedure, performed the perfusion experiments, and collected and processed tissue samples for subsequent analyses; Z.V. and S.G.D. performed the MRI studies and analyzed the data;
Noninvasive imaging strategies will be critical for defining the temporal characteristics of angiogenesis and assessing efficacy of angiogenic therapies. The alphavbeta3 integrin is expressed in angiogenic vessels and represents a potential novel target for imaging myocardial angiogenesis. We demonstrated the localization of an indium-111-labeled ((111)In-labeled) alphavbeta3-targeted agent in the region of injury-induced angiogenesis in a chronic rat model of infarction. The specificity of the targeted alphavbeta3-imaging agent for angiogenesis was established using a nonspecific control agent. The potential of this radiolabeled alphavbeta3-targeted agent for in vivo imaging was then confirmed in a canine model of postinfarction angiogenesis. Serial in vivo dual-isotope single-photon emission-computed tomographic (SPECT) imaging with the (111)In-labeled alphavbeta3-targeted agent demonstrated focal radiotracer uptake in hypoperfused regions where angiogenesis was stimulated. There was a fourfold increase in myocardial radiotracer uptake in the infarct region associated with histological evidence of angiogenesis and increased expression of the alphavbeta3 integrin. Thus, angiogenesis in the heart can be imaged noninvasively with an (111)In-labeled alphavbeta3-targeted agent. The noninvasive evaluation of angiogenesis may have important implications for risk stratification of patients following myocardial infarction. This approach may also have significant clinical utility for noninvasively tracking therapeutic myocardial angiogenesis.
Deep learning has the potential to improve automatic interpretation of MPI as compared with current clinical methods.
We developed a tissue-engineered vascular graft composed of biodegradable scaffold seeded with autologous bone marrow-derived mononuclear cells (BMMCs) that is currently in clinical trial and developed analogous mouse models to study mechanisms of neovessel formation. We previously reported that seeded human BMMCs were rapidly lost after implantation into immunodeficient mice as host macrophages invaded the graft. As a consequence, the resulting neovessel was entirely of host cell origin. Here, we investigate the source of neotissue cells in syngeneic BMMC-seeded grafts, implanted into immunocompetent mouse recipients. We again find that seeded BMMCs are lost, declining to 0.02% at 14 d, concomitant with host macrophage invasion. In addition, we demonstrate using sex-mismatched chimeric hosts that bone marrow is not a significant source of endothelial or smooth muscle cells that comprise the neovessel. Furthermore, using composite grafts formed from seeded scaffold anastomosed to sex-mismatched natural vessel segments, we demonstrate that the adjacent vessel wall is the principal source of these endothelial and smooth muscle cells, forming 93% of proximal neotissue. These findings have important implications regarding fundamental mechanisms underlying neotissue formation; in this setting, the tissue-engineered construct functions by mobilizing the body's innate healing capabilities to "regenerate" neotissue from preexisting committed tissue cells.
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