Arteriogenesis versus angiogenesis: similarities and differences

Cardiovascular diseases account for more than half of total mortality before the age of 75 in industrialized countries. To develop therapies promoting the compensatory growth of blood vessels could be superior to palliative surgical surgical interventions. Therefore, much effort has been put into investigating underlying mechanisms. Depending on the initial trigger, growth of blood vessels in adult organisms proceeds via two major processes, angiogenesis and arteriogenesis. While angiogenesis is induced by hypoxia and results in new capillaries, arteriogenesis is induced by physical forces, most importantly fluid shear stress. Consequently, chronically elevated fluid shear stress was found to be the strongest trigger under experimental conditions. Arteriogenesis describes the remodelling of pre-existing arterio-arteriolar anastomoses to completely developed and functional arteries. In both growth processes, enlargement of vascular wall structures was proposed to be covered by proliferation of existing wall cells. Recently, increasing evidence emerges, implicating a pivotal role for circulating cells, above all blood monocytes, in vascular growth processes. Since it has been shown that monocytes/macrophage release a cocktail of chemokines, growth factors and proteases involved in vascular growth, their contribution seems to be of a paracrine fashion. A similar role is currently discussed for various populations of bone-marrow derived stem cells and endothelial progenitors. In contrast, the initial hypothesis that these cells -after undergoing a (trans-)differentiation- contribute by a structural integration into the growing vessel wall, is increasingly challenged

A Critical Review of Clinical Arteriogenesis Research

In human hearts, an extensive pre-existing collateral network is present. This was shown unequivocally some 50 years ago in a series of very detailed post-mortem angiographic studies. In these studies, it was also observed that the pre-existent collateral vessels enlarge upon closure of an epicardial coronary artery, resulting in large collateral conduit arteries, in sharp contrast to earlier claims that human coronary arteries are functional end arteries. These insights still form the basis for the concept of arteriogenesis as positive remodeling of pre-existent arteriolar connections. Subsequent experimental studies disclosed the putative role of circulating cells, especially monocytes, which invade the proliferating vessel wall and secrete growth factors, degrading enzymes and survival factors that are required for the development of a mature collateral circulation. Experimental stimulation of arteriogenesis is feasible but to date a relatively low number of clinical studies, with no or limited success, have been performed. The use of intracoronary derived collateral flow index can increase the sensitivity to detect the effects of pharmacological compounds on arteriogenesis, which is important in first proof-of-principle studies. These invasive measurements also allow the detection of patients with an innate defect in their arteriogenic response to coronary obstruction. In a reversed bedside-to-bench approach, the characterization of ribonucleic acid and protein expression patterns in these patients generated new targets for therapeutic arteriogenesis

Activation of the integrins α5β1 and αvβ3 and focal adhesion kinase (FAK) during arteriogenesis

Migration and proliferation of smooth muscle cells (SMC) are important events during arteriogenesis, but the underlying mechanism is still only partially understood. The present study investigates the expression of integrins α5β1 and vβ3 as well as focal adhesion kinase (FAK) and phosphorylated FAK (pY397), key mediators for cell migration and proliferation, in collateral vessels (CV) in rabbit hind limbs induced by femoral ligation or an arteriovenous (AV) shunt created between the distal femoral artery stump and the accompanying femoral vein by confocal immunofluorescence. In addition, the effect of the extracellular matrix components fibronectin (FN), laminin (LN), and Matrigel on expression of these focal adhesion molecules proliferation was studied in cultured SMCs. We found that: (1) in normal vessels (NV), both integrins α5β1 and αvβ3 were mainly expressed in endothelial cells, very weak in smooth muscle cells (SMC); (2) in CVs, both α5β1 and αvβ3 were significantly upregulated (P < 0.05); this was more evident in the shunt-side CVs, 1.5 and 1.3 times higher than that in the ligation side, respectively; (3) FAK and FAK(py397) were expressed in NVs and CVs in a similar profile as was α5β1 and αvβ3; (4) in vitro SMCs cultured on fibronectin (overexpressed in collaterals) expressed higher levels of FAK, FAK (pY397), α5β1, and αvβ3 than on laminin, whereas SMCs growing inside Matrigel expressed little of these proteins and showed no proliferation. In conclusion, our data demonstrate for the first time that the integrin-FAK signaling axis is activated in collateral vessels and that altered expression of FN and LN may play a crucial role in mediating the integrin-FAK signaling pathway activation. These findings explain a large part of the positive remodeling that collateral vessels undergo under the influence of high fluid shear stress

Towards dry machining of titanium-based alloys : A new approach using an oxygen-free environment

In the current study, the potential of dry machining of the titanium alloy Ti-6Al-4V with uncoated tungsten carbide solid endmills was explored. It is demonstrated that tribo-oxidation is the dominant wear mechanism, which can be suppressed by milling in an extreme high vacuum adequate (XHV) environment. The latter was realized by using a silane-doped argon atmosphere. In the XHV environment, titanium adhesion on the tool was substantially less pronounced as compared to reference machining experiments conducted in air. This goes hand in hand with lower cutting forces in the XHV environment and corresponding changes in chip formation. The underlying mechanisms and the ramifications with respect to application of this approach to dry machining of other metals are discussed. © 2020, MDPI AG. All rights reserved

Towards dry machining of titanium-based alloys: a new approach using an oxygen-free environment

In the current study, the potential of dry machining of the titanium alloy Ti-6Al-4V with uncoated tungsten carbide solid endmills was explored. It is demonstrated that tribo-oxidation is the dominant wear mechanism, which can be suppressed by milling in an extreme high vacuum adequate (XHV) environment. The latter was realized by using a silane-doped argon atmosphere. In the XHV environment, titanium adhesion on the tool was substantially less pronounced as compared to reference machining experiments conducted in air. This goes hand in hand with lower cutting forces in the XHV environment and corresponding changes in chip formation. The underlying mechanisms and the ramifications with respect to application of this approach to dry machining of other metals are discussed

Live in vivo imaging of Egr-1 promoter activity during neonatal development, liver regeneration and wound healing

Background: The zinc finger transcription factor Egr-1 (Early growth response 1) is central to several growth factors and represents an important activator of target genes not only involved in physiological processes like embryogenesis and neonatal development, but also in a variety of pathophysiological processes, for example atherosclerosis or cancer. Current options to investigate its transcription and activation in vivo are end-point measurements that do not provide insights into dynamic changes in the living organism. Results: We developed a transgenic mouse (Egr-1-luc) in which the luciferase reporter gene is under the control of the murine Egr-1 promoter providing a versatile tool to study the time course of Egr-1 activation in vivo. In neonatal mice, bioluminescence imaging revealed a high Egr-1 promoter activity reaching basal levels three weeks after birth with activity at snout, ears and paws. Using a model of partial hepatectomy we could show that Egr-1 promoter activity and Egr-1 mRNA levels were increased in the regenerating liver. In a model of wound healing, we demonstrated that Egr-1 promoter activity was upregulated at the site of injury. Conclusion: Taken together, we have developed a transgenic mouse model that allows real time in vivo imaging of the Egr-1 promoter activity. The ability to monitor and quantify Egr-1 activity in the living organism may facilitate a better understanding of Egr-1 function in vivo. Additional File 1: BLI of adult Egr-1-luc mice with opened body cavity. Transgenic Egr-1-luc mice (one month old) received 6 mg luciferin in 100 &#956;l PBS by intraperitoneal injection. Ten minutes thereafter the animal was killed by cervical dislocation, the body cavity opened immediately, skin from the ventral side partially removed and BLI measurement was carried out (10 min signal collection, setting 'high resolution'). A representative animal is shown with similar amplification setting as in Figure 2A

Histamine 2 Receptor Agonism and Histamine 4 Receptor Antagonism Ameliorate Inflammation in a Model of Psoriasis

Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferative keratinocytes and immune cell infiltration into the skin, often accompanied by itch. Histamine, acting via histamine 1–4 receptors, is known to modulate immune responses in the skin and to induce itch. The aim of this study was to test the role of histamine 2 receptors and histamine 4 receptors in the imiquimod-induced psoriasis-like skin inflammation model. BALB/c mice were treated intraperitoneally with amthamine (histamine 2 receptor agonist), JNJ-39758979 (histamine 4 receptor antagonist), a combination of both, or vehicle twice daily in a preventive manner. Imiquimod was applied once daily onto the back skin for 10 consecutive days. Stimulation of histamine 2 receptors and blockade of histamine 4 receptors ameliorated imiquimod-induced skin inflammation. The combination of amthamine and JNJ-39758979 reduced skin inflammation even more pronounced, diminished epidermal hyperproliferation, and inhibited spontaneous scratching behaviour. A combination of histamine 2 receptor agonist and histamine 4 receptor antagonists could represent a new strategy for the treatment of psoriasis