Neuronal migrations along glial fibers provide a primary pathway for the formation of cortical laminae. To examine the mechanisms underlying glial-guided migration, we analyzed the dynamics of cytoskeletal and signaling components in living neurons. Migration involves the coordinated two-stroke movement of a perinuclear tubulin 'cage' and the centrosome, with the centrosome moving forward before nuclear translocation. Overexpression of mPar6alpha disrupts the perinuclear tubulin cage, retargets PKCzeta and gamma-tubulin away from the centrosome, and inhibits centrosomal motion and neuronal migration. Thus, we propose that during neuronal migration the centrosome acts to coordinate cytoskeletal dynamics in response to mPar6alpha-mediated signaling.
Bovine pericardium is widely used in surgery and is commonly used for a patch after arteriotomy during cardiovascular surgery. Bovine pericardial patches have several advantages compared to prosthetic patches, including superior biocompatability, easy handling, less suture line bleeding and possibly reduced rates of infection. These advantages of bovine pericardium have led to its common use during carotid endarterectomy. However, long-term clinical results reported after carotid endarterectomy have suggested several issues that may be related to the patch including restenosis, pseudoaneurysm formation, infection, fibrosis, calcification and thrombosis. These complications may diminish the long-term efficacy of carotid endarterectomy and suggest potential areas for improvement of surgical patches. Understanding the mechanisms by which bovine pericardium heals after patch angioplasty may lead to next generation tissue engineered patches.Bovine pericardium (BP) has come into common clinical use during the past 20 years, especially when used as a patch for arterial closure during vascular and cardiac surgery. Bovine pericardial patches possess many technical merits that have led to their widespread adoption in the operating room, including easy handling, less suture bleeding and the ability to immediately perform arterial duplex examination at the site of angioplasty. However, long-term results of this biomaterial are poorly documented and need cautious interpretation as to whether its long term performance is related to the material itself or to the operation in which it is used. For example, it is unclear whether restenosis after carotid endarterectomy is directly related to the patch itself or whether restenosis is an inevitable consequence of the arterial procedure. In addition, there are sporadic reports of unusual complications with BP patches, including patch rupture and cartilaginous metaplasia. Although these reports are Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. unusual, careful examination of these potential areas of improvement may lead to future generations of BP patches with superior performance. NIH Public AccessThe native structure of bovine pericardium has three layers: 1) the serosa, the inner thin layer consisting of mesothelial cells; 2) the fibrosa, the thicker layer formed by diversely oriented, wavy bundles of collagen and elastin; and 3) the epipericardial connective tissue layer, the outer layer that is partly continuous with the pericardiosternal ligaments. Commercially available patches are processed to be acellular, preventing transpl...
For patients with coronary artery disease or limb ischemia, placement of a vein graft as a conduit for a bypass is an important and generally durable strategy among the options for arterial reconstructive surgery. Vein grafts adapt to the arterial environment; limited formation of intimal hyperplasia in the vein graft wall is thought to be an important component of successful vein graft adaptation. However, it is also known that abnormal, or uncontrolled, adaptation may lead to abnormal vessel wall remodeling with excessive neointimal hyperplasia, and ultimately vein graft failure and clinical complications. Therefore, understanding the venous-specific pathophysiological and molecular mechanisms of vein graft adaptation are important for clinical vein graft management. Of particular importance, it is currently unknown whether several specific distinct molecular differences in venous mechanisms of adaptation exist that are distinct from arterial post-injury responses; in particular, the participation of the venous marker Eph-B4 and the vascular protective molecule Nogo-B may be involved in mechanisms of vessel remodeling specific to the vein. In this review, we describe 1) venous biology from embryonic development to the mature quiescent state; 2) sequential pathologies of vein graft neointima formation; and 3) novel candidates for strategies of vein graft management. We believe that the scientific inquiry of venous-specific adaptation mechanisms will ultimately provide improvements in vein graft outcomes.
Background During vein graft adaptation to the arterial circulation, vascular endothelial growth factor (VEGF)-A expression transiently increases before becoming down-regulated; however the role of VEGF-A in venous remodeling is not clear. In addition, although VEGF-A stimulates angiogenesis and determines arterial identity in nascent arterial endothelial cells (EC), the role of VEGF-A in regulating identity in adult venous EC is also not clear. Materials and Methods EC, wild type (EphB4+/+) or heterozygous knockout (EphB4+/−), were stimulated with VEGF-A (0–100ng/ml) and examined with qPCR and Western blotting. Results VEGF-A (100ng/ml) inhibited expression of EphB4 and stimulated expression of dll4 but did not stimulate either notch or EphrinB2 expression in adult venous EC. Pretreatment with VEGFR2 neutralizing antibody abolished VEGF-stimulated down-regulation of EphB4 but not the up-regulation of Dll4. Pretreatment with PD98059 or wortmannin showed that VEGF-A down-regulation of EphB4 and up-regulation of dll4 are MEK-ERK-dependent but PI3k-Akt-independent. Compared to VEGF-induced EphB4 down-regulation and Dll4 up-regulation in control EC, reduced EphB4 signaling in EphB4+/− EC showed even further down-regulation of EphB4 and up-regulation of dll4. Conclusions Despite the genetic programming of arterial and venous EC fate, VEGF-A can repress venous identity in adult venous EC without induction of arterial identity. These changes in adult EC in vitro recapitulate the changes in identity described during vein graft adaptation to the arterial environment in vivo.
Alternative therapies are currently being developed to treat patients with chronic limb ischemia who are unable to be revascularized in order to avoid amputation. Cell based therapy using mononuclear cells is gaining attention as many clinical trials are currently underway. We review cell differentiation along with the different potential cell sources for use in therapeutic angiogenesis.
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