This is the first systematic analysis of VSMC differentiation in bN. The results suggest that smoothelin is the most sensitive marker for the contractile phenotype and that S100A4 could be a novel marker for the secretory phenotype in vivo. The other markers did not seem to differentiate these phenotypes in bN. Thus, VSMC phenotype markers should be defined in the context of the vessel segment and disease under examination. S100A4 could not only be a marker of pro-fibrotic secretory VSMCs in bN but also an important mediator of arteriolar fibrosis.
Atypical haemolytic-uremic syndrome (aHUS) is, in most cases, due to hereditary or acquired defects in complement regulation and a life-threatening disease. Despite the rapidly grown knowledge about the primary defects in aHUS, the pathogenesis that links complement dysregulation with microthrombus formation in aHUS is still unknown. Thus, we examined the glomerular microvascular expression of pro- and antithrombotic genes. Glomeruli were microdissected from 12 archival paraffin-embedded biopsies with aHUS and from seven control biopsies. Glomerular mRNA expression was quantified by single real-time PCR reactions after preamplification. In addition immunostains were performed for plasminogen activator inhibitor 1 (PAI-1) and for tissue plasminogen activator (tPA). Results were compared between cases and controls and with clinical data. Glomeruli in aHUS had increased mRNA expression of antifibrinolytic, prothrombotic PAI-1, antithrombotic thrombomodulin (THBD) and CD73 and decreased expression of profibrinolytic, antithrombotic tPA compared to controls. Impaired fibrinolysis due to increased microvascular expression of the antifibrinolytic PAI-1 in combination with the decreased expression of the profibrinolytic tPA seems to be a final common pathway in renal thrombotic microangiopathy that is also effective in aHUS. The concomitant induction of antithrombotic transcripts likely indicates counterregulatory efforts, demonstrating that the capillary bed is not a passive victim of complement attack. Future research should investigate if and how complement activation could induce the reported shift in the expression of PAI-1 and tPA.
Background. ESWT has proven clinical benefit in dermatology and plastic surgery. It promotes wound healing and improves tissue regeneration, connective tissue disorders, and inflammatory skin diseases. However, a single treatment session or long intervals between sessions may reduce the therapeutic effect. The present study investigated the effects of fractionated repetitive treatment in skin microcirculation. Methods. 32 rats were randomly assigned to two groups and received either fractionated repetitive high-energy ESWT every ten minutes or placebo shock wave treatment, applied to the dorsal lower leg. Microcirculatory effects were continuously assessed by combined laser Doppler imaging and photospectrometry. Results. In experimental group, cutaneous tissue oxygen saturation was increased 1 minute after the first application and until the end of the measuring period at 80 minutes after the second treatment (P < 0.05). The third ESWT application boosted the effect to its highest extent. Cutaneous capillary blood flow showed a significant increase after the second application which was sustained for 20 minutes after the third application (P < 0.05). Placebo group showed no statistically significant differences. Conclusions. Fractionated repetitive extracorporeal shock wave therapy (frESWT) boosts and prolongs the effects on cutaneous hemodynamics. The results indicate that frESWT may provide greater benefits in the treatment of distinct soft tissue disorders compared with single-session ESWT.
The hypothesis of this study was confirmed. This is the first study to show significant differences of cutaneous microcirculation at the dorsum of the hand within different age groups. Further clinical trials are needed in order to examine if delayed wound healing can be correlated to impaired cutaneous microcirculation at the dorsum of the hand.
The present results establish ADAMTS13 as a novel marker of contractile VSMCs that is retained in early hyalinotic bN but partially lost later in fibrotic bN. Loss of ADAMTS13 and accumulation of VWF in fibrotic but not hyalinotic arteriolar walls could further propagate fibrosis in bN.
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