Controlling the angiogenic switch in developing atherosclerotic plaques: Possible targets for therapeutic intervention (original) (raw)
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Plaque neovascularization: defense mechanisms, betrayal, or a war in progress
Annals of the New York Academy of Sciences, 2012
Angiogenesis is induced from sprouting of preexisting endothelial cells leading to neovascularization. Imbalance in the angiogenic and antiangiogenic mediators triggers angiogenesis, which may be physiological in the normal state or pathological in malignancy and atherosclerosis. Physiologic angiogenesis is instrumental for restoration of vessel wall normoxia and resolution inflammation, leading to atherosclerosis regression. However, pathological angiogenesis enhances disease progression, increasing macrophage infiltration and vessel wall thickness, perpetuating hypoxia and necrosis. In addition, thin-walled fragile neovessels may rupture, leading to intraplaque hemorrhage. Lipid-rich red blood cell membranes and free hemoglobin are detrimental to plaque composition, increasing inflammation, lipid core expansion, and oxidative stress. In addition, associated risk factors that include polymorphysms in the haptoglobin genotype and diabetes mellitus may modulate the features of plaque vulnerability. This review will focus on physiological and pathological angiogenesis in atherosclerosis and summarizes the current status of antivascular endothelial growth factor (VEGF) therapy, microvascular rarefaction, and possible statin-mediated effects in atherosclerosis neovascularization.
IBC’s 6th Annual Conference on Angiogenesis: Novel Therapeutic Developments
Expert Opinion on Investigational Drugs, 2001
Angiogenesis is a process that is dependent upon coordinate production of angiogenesis stimulatory and inhibitory (angiostatic) molecules. Any imbalance in this regulatory circuit may lead to the development of a number of angiogenesis-mediated diseases. Angiogenesis is a multi-step process including activation, adhesion, migration, proliferation and transmigration of endothelial cells across cell matrices to or from new capillaries and from existing vessels. Angiogenesis is a process involved in the formation of new vessels by sprouting from pre-existing vessels. In contrast, vessel rudiments are sorted by a process termed vasculogenesis. Endothelial heterogeneity and organ specificity might contribute to differences in the response to different anti-angiogenic mechanisms (cultured EC versus microvascular EC isolated from different tissues). Under normal physiological conditions in mature organisms, endothelial cell turnover or angiogenesis is extremely slow (from months to years). However, angiogenesis can be activated for a limited time in certain situations such as wound healing and ovulation. In certain pathological states, such as human metastasis (oncology) and ocular neovascularisation, disorders including diabetic retinopathy and age-related macular degeneration (ophthalmology), there is excessive and sustained angiogenesis. Hence, understanding the mechanisms involved in the regulation of angiogenesis could have a major impact in the prevention and treatment of pathological angiogenic processes. Additionally, endothelial cells play a major role in the modelling of blood vessels. The interplay of growth factors, cell adhesion molecules, matrix proteases and specific signal transduction pathways either in the maintenance of the quiescent state or in the reactivation of endothelial cells is critical in physiological and pathological angiogenic processes.
Non-productive angiogenesis disassembles Aß plaque-associated blood vessels
Nature Communications
The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascu...
Arteriosclerosis, Thrombosis, and Vascular Biology, 2004
Objective-To characterize the molecules and the mechanisms regulating the neoangiogenetic process in advanced atherosclerotic plaques. Methods and Results-Western blot and immunofluorescence analysis of atherosclerotic specimens demonstrated that unlike neovessels from early lesions that expressed vascular endothelial growth factor (VEGF) and angiopoietin1 (Angio1), vessels from advanced lesions expressed VEGF and angiopoietin 2 (Angio2). Moreover, only few neovessels from advanced lesions showed a positive immunostaining for proliferating cell nuclear antigen. Angio1-elicited and Angio2-elicited intracellular events in endothelial cells (EC) demonstrated that while Angio1 triggered Erk1/Erk2 mitogen activated protein kinases (MAPK) and Akt activation, Angio2 (50 ng/mL) induced STAT5 activation and p21 waf expression and increased the fraction of cells in G1. Both Angio2-mediated events were abrogated by expressing a dominant negative STAT5 construct (⌬STAT5). Consistent with the expression of Angio2 in neovessels of advanced lesions a transcriptionally active STAT5 was detected. Moreover, co-immunoprecipitation experiments revealed the presence of a STAT5/Tie2 molecular complex in neointima vessels from advanced, but not from early, lesions.
Mouse models to study angiogenesis in the context of cardiovascular diseases
Frontiers in Bioscience, 2009
Pathological angiogenesis is a hallmark of various ischemic diseases (insufficient vessel growth) but also of cancer and metastasis, inflammatory diseases, blindness, psoriasis or arthritis (excessive angiogenesis). In response to ischemia (reduced blood flow and oxygen supply), new blood vessels form in order to compensate for the lack of perfusion. This natural process could protect them from the consequences of atherosclerotic diseases (myocardial angina, infarction, hindlimb arteriopathy or stroke). However, neovessel formation is altered in many patients. A better understanding of the mechanisms of functional vessel formation is a pre-requisite to improving the treatment of ischemic pathologies. To this end, it is essential to create easily accessible animal models in which vessel formation can be both manipulated and studied. In this review, we will describe different angiogenic mouse models in the context of cardiovascular diseases, either in an ischemic context (hindlimb ischemia, heart ischemia,
Atherosclerotic plaque development: Disease Pathogenesis and emerging treatment options
Atherosclerosis is a process of plaque formation and it manifest into different cardiovascular diseases. Basic mechanism that helps in Artherogenesis are Trans-migration of different granulocytes in the intimal layer of the artery with the help of adhesion molecules expressed in the outer layer of the activated endothelium. Excess circulatory Low Density Lipoprotein (LDL) enters the intimal layer via dysfunctional endothelium and gets oxidized into Oxidized-Low Density Lipoprotein (OX-LDL) and further entrapment of OXLDL leads to macrophage to foam cell conversion on a gradual feeling on the OX-LDL in the intima. Foam cell formation leads to series of enzymatic Reactive Oxygen Species (ROS), scavenging receptors and chemokine’s production and ultimately leading towards the oxidative pathways which end up in the inflammation and further complications leading towards several different cardiovascular diseases.
Role of Angiogenesis in Cardiovascular Disease A Critical Appraisal
2000
The role of angiogenesis in atherosclerosis and other cardiovascular diseases has emerged as a major unresolved issue. Angiogenesis has attracted interest from opposite perspectives. Angiogenic cytokine therapy has been widely regarded as an attractive approach both for treating ischemic heart disease and for enhancing arterioprotective functions of the endothelium; conversely, a variety of studies suggest that neovascularization contributes to the growth of atherosclerotic lesions and is a key factor in plaque destabilization leading to rupture. Here, we critically review the evidence supporting a role for angiogenesis and angiogenic factors in atherosclerosis and neointima formation, emphasizing the problems raised by some of the landmark studies and the suitability of animal models of atherosclerosis and neointimal thickening for investigating the role of angiogenesis. Because many of the relevant studies have focused on the role of vascular endothelial growth factor (VEGF), we consider this work in the wider context of VEGF biology and in light of recent experience from clinical trials of VEGF and other angiogenic cytokines for ischemic heart disease. Also discussed are recent findings suggesting that, although angiogenesis may contribute to neointimal growth, it is not required for the initiation of intimal thickening. Our assessment of the evidence leads us to conclude that, although microvessels are a feature of advanced human atherosclerotic plaques, it remains unclear whether angiogenesis either plays a central role in the development of atherosclerosis or is responsible for plaque instability. Furthermore, current evidence from clinical trials of both proangiogenic and antiangiogenic therapies does not suggest that inhibition of angiogenesis is likely to be a viable therapeutic strategy for cardiovascular disease.
Arteriosclerosis, Thrombosis, and Vascular Biology, 1999
Recent information indicates that platelet-derived endothelial cell growth factor (PD-ECGF), a 45-kDa angiogenic protein, is expressed in the endothelium of various tissues and that its level of expression is correlated with the number of microvessels in human tumors. Because the formation of neovessels is also thought to play a role in atherosclerotic vascular remodeling, we analyzed PD-ECGF expression in fresh, coronary plaque tissues obtained by directional coronary atherectomy. Specimens from 31 patients were collected and analyzed by reverse transcriptionpolymerase chain reaction, histochemical staining, immunohistochemistry, and in situ hybridization with the use of PD-ECGF-specific primers and probes. Lesional vascular remodeling was assessed by intravascular ultrasound. PD-ECGF immunoreactivity and mRNA were found in plaque macrophages, endothelial cells of plaque neovessels, and stellate smooth muscle cells of 20 atherectomy specimens (64.5%). PD-ECGF immunoreactivity was correlated with the number of lesional microvessels and mast cells. Double-staining experiments revealed a close spatial proximity of PD-ECGF-positive cells and mast cells. Furthermore, the numbers of microvessels and mast cells were significantly higher in lesions lacking compensatory enlargement. The data indicate that PD-ECGF is expressed within cells of the atherosclerotic plaque and may be involved in driving angiogenesis in concert with mast cells.