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Small-vessel vasculitis (SVV) is the inflammation of the vessel wall that can result in hemorrhage and/or ischemia. Among the histological findings in SVV are increased infiltrating neutrophils, which, due to their oxidative burst and myeloperoxidase activity, release excessive reactive oxygen species, triggering a chain reaction of lipid peroxidation and yielding reactive aldehydes such as acrolein. The implication of oxidative stress in the pathogenesis of SVV was studied, focusing on acrolein immunohistochemistry in the affected skin vessels and systemic stress response. Samples from SVV patients and healthy subjects were collected and analyzed for total serum peroxides, total antioxidant capacity, inflammatory and immunological parameters, as well as for the presence of acrolein–protein adducts in the skin tissue specimens. The obtained data showed that systemic redox homeostasis and iron metabolism are altered in SVV patients. Possible biomarkers in the evaluation of oxidative status, disease activity and prevalence were indicated. Furthermore, a strong correlation between the accumulation of acrolein–protein adducts in the skin and the progression of the disease was revealed. Thus, the results of this study demonstrate that SVV is not only associated with systemic oxidative stress but also with tissue-specific oxidative stress that promotes acrolein formation and protein modification correlating with the severity of cutaneous vasculitis.

Aging is associated with an altered regulation of blood flow to contracting skeletal muscle; however, the precise mechanisms remain unclear. We recently demonstrated that inhibition of cGMP-binding phosphodiesterase 5 (PDE5) increased blood flow to contracting skeletal muscle of older but not young human subjects. Here we examined whether this effect of PDE5 inhibition was related to an improved ability to blunt α-adrenergic vasoconstriction (functional sympatholysis) and/or improved efficacy of local vasodilator pathways. A group of young (23 ± 1 yr) and a group of older (72 ± 1 yr) male subjects performed knee-extensor exercise in a control setting and following intake of the highly selective PDE5 inhibitor sildenafil. During both conditions, exercise was performed without and with arterial tyramine infusion to evoke endogenous norepinephrine release and consequently stimulation of α1- and α2-adrenergic receptors. The level of the sympatholytic compound ATP was measured in venous plasma by use of the microdialysis technique. Sildenafil increased ( P < 0.05) vascular conductance during exercise in the older group, but tyramine infusion reduced ( P < 0.05) this effect by 38 ± 9%. Similarly, tyramine reduced ( P < 0.05) the vasodilation induced by arterial infusion of a nitric oxide (NO) donor by 54 ± 9% in the older group, and this effect was not altered by sildenafil. Venous plasma [ATP] did not change with PDE5 inhibition in the older subjects during exercise. Collectively, PDE5 inhibition in older humans was not associated with an improved ability for functional sympatholysis. An improved efficacy of the NO system may be one mechanism underlying the effect of PDE5 inhibition on exercise hyperemia in aging.

The master mammalian circadian clock (i.e. central clock), located in the suprachiasmatic nucleus of the hypothalamus, orchestrates the synchronization of the daily behavioural and physiological rhythms to better adapt the organism to the external environment in an anticipatory manner. This central clock is entrained by a variety of signals, the best established being light and food. However, circadian cycles are not simply the consequences of these two cues but are generated by endogenous circadian clocks. Indeed, clock machinery is found in mainly all tissues and cell types, including cells of the vascular system such as endothelial cells, fibroblasts, smooth muscle cells and stem cells. This machinery physiologically contributes to modulate the daily vascular function, and its disturbance therefore plays a major role in the pathophysiology of vascular dysfunction. Therapies targeting the circadian rhythm may therefore be of benefit against vascular disease.

To improve well-known titanium implants, pores can be used for increasing bone formation and close bone-implant interface. Selective Laser Melting (SLM) enables the production of any geometry and was used for implant production with 250-microm pore size. The used pore size supports vessel ingrowth, as bone formation is strongly dependent on fast vascularization. Additionally, proangiogenic factors promote implant vascularization. To functionalize the titanium with proangiogenic factors, polycaprolactone (PCL) coating can be used. The following proangiogenic factors were examined: vascular endothelial growth factor (VEGF), high mobility group box 1 (HMGB1) and chemokine (C-X-C motif) ligand 12 (CXCL12). As different surfaces lead to different cell reactions, titanium and PCL coating were compared. The growing into the porous titanium structure of primary osteoblasts was examined by cross sections. Primary osteoblasts seeded on the different surfaces were compared using Live Cell Imaging (LCI). Cross sections showed cells had proliferated, but not migrated after seven days. Although the cell count was lower on titanium PCL implants in LCI, the cell count and cell spreading area development showed promising results for titanium PCL implants. HMGB1 showed the highest migration capacity for stimulating the endothelial cell line. Future perspective would be the incorporation of HMGB1 into PCL polymer for the realization of a slow factor release. DFG/299/11-1

We describe our observations concerning differences in two groups of young hypertensive patients according to their renin activities after ACE inhibition. Seventeen of these patients (age 26 +/- 7 years), so far untreated, were investigated prospectively for hormone levels (renin, aldosterone, vasopressin), microalbuminuria, renal haemodynamics (inulin and PAH clearance) and signs of organ damage (echocardiography, fundoscopy). Secondary forms of hypertension were excluded by routine methods, including angiography. We differentiated two groups of young hypertensive patients. Group 1 (n = 9) had a false positive captopril test with elevated renin activities after ACE inhibition with captopril (8.4 +/- 5 ng/ml per hour) compared to group 2 (renin activity: 2.2 +/- 1.3 ng/ml per hour) or an increase of greater than 400% of renin activity after ACE inhibition. Baseline renin activities and sodium excretion did not differ between the groups. Group 1 also showed significantly greater GFR, FF, and microalbuminuria, as well as signs of organ damage, with left ventricular hypertrophy and hypertensive changes in fundoscopy. There were no differences between the groups concerning mean arterial blood pressure and duration of hypertension. In conclusion, we were able to demonstrate that patients with highly stimulated renin activities showed signs of visceral organ damage and renal hyperfiltration compared to the normal renin activity group after ACE inhibition. Investigations of the renin-angiotensin-aldosterone system with ACE inhibitors might constitute a helpful indicator of renal changes and organ damages in young hypertensive patients.

Suloctidil is a calcium antagonist with vascular relaxing activity and an antithrombotic agent: its antiplatelet action has been demonstrated in vivo, but is difficult to reproduce in vitro and the mechanism of this effect remains unknown. We have observed that suloctidil (10 microM) stimulated the release of prostacyclin (PGI2) from the rabbit aorta, the dog vena cava and the dog portal vein, in vitro. This effect could be explained by an increased mobilization of free arachidonic acid. Neither the inactive congener CP894S, nor the two calcium channel antagonists, verapamil and flunarizine, reproduced the stimulatory effect of suloctidil. Suloctidil acted selectively on the vascular endothelium: it stimulated the release of PGI2 from bovine aortic and human umbilical vein endothelial cells, but neither from the de-endothelialized rabbit aorta nor from the bovine aortic media. The stimulatory effect of suloctidil on the release of the platelet inhibitor PGI2 from the vascular endothelium might contribute to the known antiplatelet and antithrombotic activity of this drug., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

The action of dipyridamole on the vascular production of prostacyclin (PGI2) has been investigated. Dipyridamole (1-100 microM) did not induce a significant stimulation of PGI2 release in any of the following experimental models: rings of rabbit aorta, cultured endothelial cells from bovine aorta or human umbilical vein, cultured explants of bovine aortic smooth muscle. The activity of known stimuli of PGI2 release (ADP, suloctidil, serotonin) and the capacity of dipyridamole to inhibit adenosine uptake into endothelial cells were carefully checked. Pretreatment of the rabbit aorta with dipyridamole (10-100 microM) prolonged the transient stimulation of PGI2 release induced by mechanical deendothelialization: this effect was probably due to a partial protection of the cyclooxygenase against oxidative self-inactivation. Our largely negative results are consistent with the current theory that the antiplatelet action of dipyridamole is mediated by adenosine and not by PGI2., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published