Regulation Of Vascular Inflammation Research Articles

Endothelin-1 is Elevated in Alzheimer's Disease Brain Microvessels and is Neuroprotective

The vasoactive protein endothelin-1 (ET-1) is produced by vascular endothelial cells and participates in the regulation of vascular inflammation. We have previously documented that the cerebral microvasculature is a source of inflammatory proteins and a likely contributor to the pathogenesis of Alzheimer's disease (AD). In this study, we (a) compare expression of ET-1 in brain microvessels isolated from AD and control brains; (b) determine thrombin regulation of ET-1 synthesis and release in brain endothelial cells; and (c) assess the effects of ET-1 on neuronal viability in vitro. Western blot analysis indicates a significantly higher level of ET-1 in AD vessels compared to vessels from age-matched controls. ET-1 expression and secretion are both induced by the inflammatory and neurotoxic protein thrombin. Pretreatment of neuronal cultures with ET-1 significantly increases neuronal survival when cells are challenged with oxidative stress (H2O2) or thrombin. The protective effect of ET-1 is blocked by incubation with an inhibitor of the c-Jun kinase (JNK) cascade. These data demonstrate that in the brain microvasculature dysfunctional or stressed endothelial cells express ET-1 and that this protein promotes the survival of brain neurons exposed to injury.

TGF-β in the pathogenesis and prevention of disease: a matter of aneurysmic proportions

TGF-beta regulates many aspects of cellular performance relevant to tissue morphogenesis and homeostasis. Postnatal perturbation of TGF-beta signaling contributes to the pathogenesis of many disease states, as recently exemplified through the study of Marfan syndrome (MFS), including aortic aneurysm and skeletal muscle myopathy. Heterogeneity in the regulation and consequences of TGF-beta signaling, amplified in the context of disease, has engendered confusion and controversy regarding its utility as a therapeutic target. Three studies recently published in the JCI, including one in this issue, underscore the complexity of this subject. Heydemann and colleagues implicate dimorphic variation in latent TGF-beta-binding protein 4 (LTBP4), a regulator of TGF-beta bioavailability and activation, as a modifier of muscular dystrophy in gamma-sarcoglycan-deficient mice. In contrast to experience with ascending aortic aneurysm in MFS, Wang and colleagues show that systemic abrogation of TGF-beta signaling worsens (rather than attenuates) Ang II-induced abdominal aortic aneurysm progression in mice. Tieu and colleagues define alterations in the regulation of vascular inflammation in the pathogenesis of Ang II-induced aneurysm and dissection in mice, which may help shed some light on this apparent paradox.

Thrombin activatable fibrinolysis inhibitor activity (TAFIa) levels in neonates with meconium-stained amniotic fluid

Objective. Meconium-stained amniotic fluid (MSAF) is thought to be a sign of fetal hypoxia, which causes activation of coagulation and inhibition of fibrinolysis. Inflammation is also seen in MSAF. On the other hand, thrombin activatable fibrinolysis inhibitor (TAFI) is an inhibitor of fibrinolysis and a regulator of vascular inflammation. For this reason, in this study we aimed to evaluate the relation between hypoxia, fibrinolysis, and inflammation by determining the levels of TAFI activity (TAFIa) in MSAF where inflammation was also thought to have a role in the pathogenesis.Methods. The MSAF group consisted of 22 neonates; 20 neonates served as the control group. Plasma TAFIa levels were evaluated in all neonates in the first six hours of life.Results. TAFIa levels were significantly higher in the MSAF group when compared with the control group and the levels correlated negatively with cord blood pH levels.Conclusions. Increased TAFIa levels in neonates with MSAF might be due to hypoxia. Inflammation observed in MSAF may also play an additional role in increased TAFIa expression. Although no clinical complication that can be attributed to this increase was seen, one should be alert to the complications of depressed fibrinolysis that might be observed in these neonates.

Innate immunity, macrophage activation, and atherosclerosis

Inflammation underpins the development of atherosclerosis. Initiation and progression of vascular inflammation involves a complex cellular network, with macrophages as major contributors. Activated macrophages produce proinflammatory mediators, bridge innate and adaptive immunity, regulate lipid retention, and participate directly in vascular repair and remodeling. Recent efforts to elucidate molecular mechanisms involved in the regulation of vascular inflammation in atherosclerosis have implicated several families of innate immune recognition receptors in inflammatory activation during the course of this disease. This article reviews our current understanding of innate immune recognition receptors, signaling pathways, and putative ligands implicated in activation of macrophages in the disease. In its final section, we propose a model for the role of macrophages in bridging inflammation and atherosclerosis from the perspective of innate immune recognition and activation.

Targeted deletion of discoidin domain receptor 1 (Ddr1) decreases atherosclerosis, reduces inflammation and accelerates matrix accumulation in LDL receptor deficient mices

Background: Collagens are abundant within the atherosclerotic plaque where they contribute to lesion volume, mechanical stability, and influence cellular behaviour. The discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds multiple collagen subtypes, has been observed in atheromata of non-human primates, but its function during atherogenesis is unclear. 
 Methods: To examine the role of DDR1 during atherosclerotic plaque development, we generated Ddr1+/+;Ldlr-/- and Ddr1-/-;Ldlr-/- mice and fed them an atherogenic diet for 12 or 24 weeks. 
 Results: Targeted deletion of Ddr1 resulted in a 50-60% reduction in atherosclerotic lesion area in the descending aorta at both 12 and 24 weeks. Atherosclerotic plaques from Ddr1-/-;Ldlr-/- mice demonstrated a 49% decrease in the area occupied by macrophages at 12 weeks, however, plaque SMC content was unchanged. We also observed accelerated deposition of fibrillar collagen and elastin in Ddr1-/-;Ldlr-/- plaques with a 36% and 45% increase at 12 weeks, respectively. Ddr1-/-;Ldlr-/- mice also demonstrated an early reduction in situ gelatinolytic activity in lesions and gelatin zymography revealed reduced MMP-2 activity at 12 weeks. Finally, mRNA expression analysis of laser microdissected plaques demonstrated enhanced expression of type I collagen and elastin, and reduced collagenase expression at 12 weeks. Moreover, mRNA expression of both MCP-1 and VCAM-1 was reduced in Ddr1-/-;Ldlr-/- plaques suggesting a novel role for DDR1 in the regulation of vascular inflammation. 
 Conclusion: Our data support a role for DDR1 as a positive regulator of atherosclerosis; capable of influencing both inflammation and matrix turnover early in plaque development, and when inhibited can result in a persistent reduction in atherosclerosis.

Regulation of Vascular Inflammation and Remodeling by ETS Factors

The ETS (E26 Transformation-specific Sequence) factors are comprised of a family of transcription factors that share a highly conserved DNA binding domain. Although originally described for their role as protooncogenes in the development of several types of human cancer, they have subsequently been shown to regulate a wide variety of biological processes including cellular growth and differentiation under normal and pathological conditions. As transcription factors, they can either function as activators or repressors of gene expression. Several ETS family members are expressed in cells of vascular origin, including endothelial cells and vascular smooth muscle cells, where they regulate the expression of a number of vascular-specific genes. In the past few years, emerging evidence supports a novel role for selected ETS family members in the regulation of vascular inflammation and remodeling. ETS factor expression can be induced by proinflammatory cytokines, growth factors, and vasoactive peptides. Examples of some of the target genes regulated by ETS factors include adhesion molecules, chemokines, and matrix metalloproteinases. Targeted disruption of selected ETS family members such as Ets-1 in mice is associated with marked reductions in the recruitment of inflammatory cells and vascular remodeling in response to systemic administration of the vasoactive peptide angiotensin II. The purpose of this review is to provide an overview of recent advances that have been made in defining a role for selected members of the ETS transcription factor family in the regulation of vascular-specific gene expression, vascular inflammation, and remodeling.

Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury

Background It is now evident that inflammation after vascular injury has significant impact on the restenosis after revascularization procedures such as angioplasty, stenting, and bypass grafting. However, the mechanisms that regulate inflammation and repair after vascular injury are incompletely understood. Here, we report that vascular injury-mediated cytokine expression, reactive oxygen species (ROS) production, as well as subsequent neointimal formation requires Toll-like receptor-2 (TLR-2) mediated signaling pathway in vivo. Methods and results Vascular injury was induced by cuff-placement around the femoral artery in non-transgenic littermates (NLC) and TLR-2 knockout (TLR-2KO) mice. After cuff-placement in NLC mice, expression of TLR-2 was significantly increased in both smooth muscle medial layer and adventitia. Interestingly, we found that inflammatory genes expression such as tumor necrosis factor-α, interleukin-1β (IL-1β), IL-6, and monocyte chemoattractant protein-1 were markedly decreased in TLR-2KO mice compared with NLC mice. In addition, ROS production after vascular injury was attenuated in TLR-2KO mice compared with NLC mice. Since we observed the significant role of endogenous TLR-2 activation in regulating inflammatory responses and ROS production after vascular injury, we determined whether inhibition of endogenous TLR-2 activation can inhibit neointimal proliferation after vascular injury. Neointimal hyperplasia was markedly suppressed in TLR-2KO mice compared with WT mice at both 2 and 4 weeks after vascular injury. Conclusions These findings suggested that endogenous TLR-2 activation might play a central role in the regulation of vascular inflammation as well as subsequent neointimal formation in injured vessels.