Vascular walls change their dimension and mechanical properties in response to injury such as balloon angioplasty and endovascular stent implantation. Placement of bare metal stents induces ...neointimal proliferation/restenosis which progresses through different phases of repair with time involving a cascade of cellular reactions. These phases just like wound healing comprise distinct steps consisting of thrombosis, inflammation, proliferation, and migration followed by remodelling. It is noteworthy that animals show a rapid progression of healing after stent deployment compared with man. During stenting, endothelial cells are partially to completely destroyed or crushed along with medial wall injury and stretching promoting activation of platelets, and thrombus formation accompanied by inflammatory reaction. Macrophages and platelets play a central role through the release of cytokines and growth factors that induce vascular smooth muscle cell accumulation within the intima. Smooth muscle cells undergo complex phenotypic changes including migration and proliferation from the media towards the intima, and transition from a contractile to a synthetic phenotype; the molecular mechanisms responsible for this change are highlighted in this review. Since studies in animals and man show that smooth muscle cells play a dominant role in restenosis, drugs like rapamycin and paclitaxel have been coated on stent with polymers to allow local slow release of drugs, which have resulted in dramatic reduction of restenosis that was once the Achilles' heel of interventional cardiologists.
Pulmonary arterial hypertension (PAH) is an incurable disease associated with viral infections and connective tissue diseases. The relationship between inflammation and disease pathogenesis in these ...disorders remains poorly understood.
To determine whether immune dysregulation due to absent T-cell populations directly contributes to the development of PAH.
Vascular endothelial growth factor receptor 2 (VEGFR2) blockade induced significant pulmonary endothelial apoptosis in T-cell-deficient rats but not in immune-reconstituted (IR) rats. T cell-lymphopenia in association with VEGFR2 blockade resulted in periarteriolar inflammation with macrophages, and B cells even prior to vascular remodeling and elevated pulmonary pressures. IR prevented early inflammation and attenuated PAH development. IR with either CD8 T cells alone or with CD4-depleted spleen cells was ineffective in preventing PAH, whereas CD4-depleting immunocompetent euthymic animals increased PAH susceptibility. IR with either CD4(+)CD25(hi) or CD4(+)CD25(-) T cell subsets prior to vascular injury attenuated the development of PAH. IR limited perivascular inflammation and endothelial apoptosis in rat lungs in association with increased FoxP3(+), IL-10- and TGF-β-expressing CD4 cells, and upregulation of pulmonary bone morphogenetic protein receptor type 2 (BMPR2)-expressing cells, a receptor that activates endothelial cell survival pathways.
PAH may arise when regulatory T-cell (Treg) activity fails to control endothelial injury. These studies suggest that regulatory T cells normally function to limit vascular injury and may protect against the development of PAH.
MicroRNA-22 (miR-22) has recently been reported to play a regulatory role during vascular smooth muscle cell (VSMC) differentiation from stem cells, but little is known about its target genes and ...related pathways in mature VSMC phenotypic modulation or its clinical implication in neointima formation following vascular injury.
We applied a wire-injury mouse model, and local delivery of AgomiR-22 or miR-22 inhibitor, as well, to explore the therapeutic potential of miR-22 in vascular diseases. Furthermore, normal and diseased human femoral arteries were harvested, and various in vivo, ex vivo, and in vitro models of VSMC phenotype switching were conducted to examine miR-22 expression during VSMC phenotype switching.
Expression of miR-22 was closely regulated during VSMC phenotypic modulation. miR-22 overexpression significantly increased expression of VSMC marker genes and inhibited VSMC proliferation and migration, whereas the opposite effect was observed when endogenous miR-22 was knocked down. As expected, 2 previously reported miR-22 target genes, MECP2 (methyl-CpG binding protein 2) and histone deacetylase 4, exhibited a regulatory role in VSMC phenotypic modulation. A transcriptional regulator and oncoprotein, EVI1 (ecotropic virus integration site 1 protein homolog), has been identified as a novel miR-22 target gene in VSMC phenotypic modulation. It is noteworthy that overexpression of miR-22 in the injured vessels significantly reduced the expression of its target genes, decreased VSMC proliferation, and inhibited neointima formation in wire-injured femoral arteries, whereas the opposite effect was observed with local application of a miR-22 inhibitor to injured arteries. We next examined the clinical relevance of miR-22 expression and its target genes in human femoral arteries. We found that miR-22 expression was significantly reduced, whereas MECP2 and EVI1 expression levels were dramatically increased, in diseased in comparison with healthy femoral human arteries. This inverse relationship between miR-22 and MECP2 and EVI1 was evident in both healthy and diseased human femoral arteries.
Our data demonstrate that miR-22 and EVI1 are novel regulators of VSMC function, specifically during neointima hyperplasia, offering a novel therapeutic opportunity for treating vascular diseases.
Blunt abdominal aortic injury Shalhub, Sherene, MD, MPH; Starnes, Benjamin W., MD; Tran, Nam T., MD ...
Journal of vascular surgery,
05/2012, Volume:
55, Issue:
5
Journal Article
Peer reviewed
Open access
Background Blunt abdominal aortic injury (BAAI) is a rare injury with less than 200 cases in the current reported world literature, mostly in case report format. We sought to describe the experience ...of a high-volume trauma center and to provide a contemporary review of the literature to better understand the natural history and management of this injury. Methods This was a retrospective review of patients with BAAI between 1996 and 2010. Data collected included demographics, mechanism of injury, associated injuries, type of intervention, subsequent imaging, and follow-up. BAAI was classified by the presence of external aortic contour abnormality noted as an intimal tear, large intimal flap, pseudoaneurysm, or free rupture. Abdominal aorta zones of injury were classified by possible surgical approaches as zone I (diaphragmatic hiatus to superior mesenteric artery SMA), zone II (includes SMA and renal arteries), and zone III (from the inferior aspect of the renal arteries to the aortic bifurcation). Results We identified 28 individuals (68% male) with BAAI (median age, 28.5; range, 6-61 years). The median injury severity score was 45 (range, 16-75), and 39% were hypotensive at presentation. BAAI presented as intimal tear (21%), large intimal flap (39%), pseudoaneurysm (11%), and free rupture (29%). Zone III was the most common location of injury. Management depended on the location and type of injury: nonoperative (32%), open aortic repair (36%), endovascular repair (21%), and multimodality (10%). Overall mortality was 32%. Most deaths occurred during the initial operative exploration. The mortality rate of free aortic rupture was 100%. Intimal tears resolved or remained stable. Median follow-up was 15.5 months (range, 8 days-7.5 years). Vascular complications due to repair included a thrombosed access femoral artery during an endovascular repair and death of a patient who underwent a hybrid repair. Conclusions This is the largest BAAI series described in the English literature at one institution. BAAIs range from intimal tears to free rupture, with outcomes and management correlating with type and location of injury. Nonoperative management with blood pressure control using β-blockers coupled with antiplatelet therapy and close follow-up is successful in individuals with intimal tears with minimal thrombus formation because they remain stable or resolve on follow-up. Free rupture remains a devastating injury, with 100% mortality. For all other categories of aortic injury, successful repair correlates with a favorable prognosis.
Vascular remodelling and aortic aneurysm formation are induced mainly by inflammatory responses in the adventitia and media. However, relatively little is known about the mechanistic significance of ...endothelium in the pathogenesis of these vascular disorders. The transcription factor nuclear factor-kappa B (NF-κB) regulates the expressions of numerous genes, including those related to pro-inflammatory responses. Therefore, to investigate the roles of endothelial pro-inflammatory responses, we examined the impact of blocking endothelial NF-κB signalling on intimal hyperplasia and aneurysm formation.
To block endothelial NF-κB signalling, we used transgenic mice expressing dominant-negative IκBα selectively in endothelial cells (E-DNIκB mice). E-DNIκB mice were protected from the development of cuff injury-induced neointimal formation, in association with suppressed arterial expressions of cellular adhesion molecules, a macrophage marker, and inflammatory factors. In addition, the blockade of endothelial NF-κB signalling prevented abdominal aortic aneurysm formation in an experimental model, hypercholesterolaemic apolipoprotein E-deficient mice with angiotensin II infusion. In this aneurysm model as well, aortic expressions of an adhesion molecule, a macrophage marker, and inflammatory factors were suppressed with the inhibited expression and activity of matrix metalloproteinases in the aorta.
Endothelial NF-κB activation up-regulates adhesion molecule expression, which may trigger macrophage infiltration and inflammation in the adventitia and media. Thus, the endothelium plays important roles in vascular remodelling and aneurysm formation through its intracellular NF-κB signalling.
Vascular smooth muscle cell (VSMC) accumulation is a hallmark of atherosclerosis and vascular injury. However, fundamental aspects of proliferation and the phenotypic changes within individual VSMCs, ...which underlie vascular disease, remain unresolved. In particular, it is not known whether all VSMCs proliferate and display plasticity or whether individual cells can switch to multiple phenotypes.
To assess whether proliferation and plasticity in disease is a general characteristic of VSMCs or a feature of a subset of cells.
Using multicolor lineage labeling, we demonstrate that VSMCs in injury-induced neointimal lesions and in atherosclerotic plaques are oligoclonal, derived from few expanding cells. Lineage tracing also revealed that the progeny of individual VSMCs contributes to both alpha smooth muscle actin (aSma)-positive fibrous cap and Mac3-expressing macrophage-like plaque core cells. Costaining for phenotypic markers further identified a double-positive aSma+ Mac3+ cell population, which is specific to VSMC-derived plaque cells. In contrast, VSMC-derived cells generating the neointima after vascular injury generally retained the expression of VSMC markers and the upregulation of Mac3 was less pronounced. Monochromatic regions in atherosclerotic plaques and injury-induced neointima did not contain VSMC-derived cells expressing a different fluorescent reporter protein, suggesting that proliferation-independent VSMC migration does not make a major contribution to VSMC accumulation in vascular disease.
We demonstrate that extensive proliferation of a low proportion of highly plastic VSMCs results in the observed VSMC accumulation after injury and in atherosclerotic plaques. Therapeutic targeting of these hyperproliferating VSMCs might effectively reduce vascular disease without affecting vascular integrity.
Abnormal proliferation and migration of vascular smooth muscle cells (SMCs) are the key events in the progression of neointima formation in response to vascular injury. The goal of this study is to ...investigate the functional role of a potent oncogene yes-associated protein (YAP) in SM phenotypic modulation in vitro and in vivo.
In vitro cell culture and in vivo in both mouse and rat arterial injury models YAP expression is significantly induced and correlated with the vascular SMC synthetic phenotype. Overexpression of YAP promotes SMC migration and proliferation while attenuating SM contractile gene expression. Conversely, knocking down endogenous YAP in SMCs upregulates SM gene expression but attenuates SMC proliferation and migration. Consistent with this, knocking down YAP expression in a rat carotid balloon injury model and genetic deletion of YAP, specifically, in vascular SMCs in mouse after carotid artery ligation injury attenuates injury-induced SM phenotypic switch and neointima formation.
YAP plays a novel integrative role in SM phenotypic modulation by inhibiting SM-specific gene expression while promoting SM proliferation and migration in vitro and in vivo. Blocking the induction of YAP would be a potential therapeutic approach for ameliorating vascular occlusive diseases.
Despite major advances in the primary and secondary prevention of atherosclerosis and its risk factors, atherosclerotic cardiovascular disease remains a major clinical and financial burden on ...individuals and health systems worldwide. In addition, neointima formation and proliferation due to mechanical trauma to the vessel wall during percutaneous coronary interventions can lead to vascular restenosis and limit the longevity and effectiveness of coronary revascularization. Long noncoding RNAs (lncRNAs) have emerged as a novel class of epigenetic regulators with critical roles in the pathogenesis of atherosclerosis and restenosis following vascular injury. Here, we provide an in-depth review of lncRNAs that regulate the development of atherosclerosis or contribute to the pathogenesis of restenosis following mechanical vascular injury. We describe the diverse array of intracellular mechanisms by which lncRNAs exert their regulatory effects. We highlight the utility and challenges of lncRNAs as biomarkers. Finally, we discuss the immense translational potential of lncRNAs and strategies for targeting them therapeutically using oligonucleotide-based therapeutics and novel gene therapy platforms.
Stent deployment following balloon angioplasty is used routinely to treat coronary artery disease. These interventions cause damage and loss of endothelial cells (EC), and thus promote in-stent ...thrombosis and restenosis. Injured arteries are repaired (intrinsically) by locally derived EC and by circulating endothelial progenitor cells which migrate and proliferate to re-populate denuded regions. However, re-endothelialization is not always complete and often dysfunctional. Moreover, the molecular and biomechanical mechanisms that control EC repair and function in stented segments are poorly understood. Here, we propose that stents modify endothelial repair processes, in part, by altering fluid shear stress, a mechanical force that influences EC migration and proliferation. A more detailed understanding of the biomechanical processes that control endothelial healing would provide a platform for the development of novel therapeutic approaches to minimize damage and promote vascular repair in stented arteries.
Objective Blunt traumatic aortic injury is associated with significant mortality, and increased computed tomography use identifies injuries not previously detected. This study sought to define ...parameters identifying patients who can benefit from medical management. Methods We reviewed 4.5 years of blunt traumatic aortic injuries. Injury was classified as grade I (intimal flap or intramural hematoma), II (small pseudoaneurysm <50% circumference), III (large pseudoaneurysm >50% circumference), and IV (rupture/transection). Secondary signs of injury included pseudocoarctation, extensive mediastinal hematoma, and large left hemothorax. Follow-up, including computed tomography, was reviewed. Results We identified 97 patients: 31 grade I, 35 grade II, 24 grade III, and 7 grade IV; 67(69%) male; mean age 47 ± 18.8 years, mean Injury Severity Score 38.8 ± 14.6; overall survival 76 (78.4%). Secondary signs of injury were found in 30 patients. Overall, 52 (53.6%) underwent repair, 45 undergoing thoracic endovascular aortic repair, with 2 (2.22%) procedure-related deaths, and 7 undergoing open repair. Five patients undergoing thoracic endovascular aortic repair required 7 additional procedures. In 45 medically managed patients, there were 14 deaths (31%), all secondary to associated injuries. Injury Severity Scores of survivors and nonsurvivors were 33 ± 10.8 and 48.6 ± 12.8, respectively ( P < .001). Follow-up showed resolution or no change in 21 (91%) and a small increase in 2 grade I injuries. Conclusions All blunt traumatic aortic injury does not necessitate repair. Stratification by injury grade and secondary signs of injury identifies patients appropriate for medical management. Grade IV injury necessitates emergency procedures and carries high mortality. Grade III injury with secondary signs of injury should be urgently repaired; patients without secondary signs of injury may undergo delayed repair. Grade I and II injuries are amenable to medical management.
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