Rationale Although Nox5, (Nox2 homologue), has been identified in the vasculature, its regulation and functional significance remain unclear. Objectives To test if vasoactive agents regulate Nox5 through Ca2+/calmodulin-dependent processes and whether Ca2+ -sensitive Nox5, associated with Rac-1, generates superoxide (•O2−) and activates growth and inflammatory responses via MAP kinases in human endothelial cells (ECs). Methods and results Cultured ECs, exposed to AngII and ET-1 in the absence and presence of diltiazem (Ca2+ channel blocker), calmidazolium (calmodulin inhibitor) and EHT1864 (Rac-1 inhibitor), were studied. Nox5 was downregulated with siRNA. AngII and ET-1 increased Nox5 expression (mRNA and protein). Effects were inhibited by actinomycin D and cycloheximide and blunted by diltiazem, calmidazolium and low extracellular Ca2+ ([Ca2+]e). Ang II and ET-1 activated NADPH oxidase, an effect blocked by low [Ca2+]e, but not by EHT1864. Nox5 knockdown abrogated agonist-stimulated •O2− production and inhibited phosphorylation of ERK1/2, but not p38MAPK or SAPK/JNK. Nox5 siRNA blunted AngII-induced, but not ET-1-induced, upregulation of PCNA and VCAM-1, important in growth and inflammation. Conclusions Human ECs possess functionally active Nox5, regulated by AngII and ET-1 through Ca2+/calmodulin-dependent, Rac-1-independent mechanisms. Nox5 activation by AngII and ET-1 induces ROS generation and ERK 1/2 phosphorylation. Nox5 is involved in ERK1/2-regulated growth and inflammatory signaling by AngII but not by ET-1. We elucidate novel mechanisms whereby vasoactive peptides regulate Nox5 in human ECs and demonstrate differential Nox5-mediated functional responses by AngII and ET-1. Such phenomena link Ca2+/calmodulin to Nox5 signaling, potentially important in the regulation of endothelial function by AngII and ET-1.

PurposeThe purpose of this study was to identify the causes of failure of previous medial patellofemoral ligament reconstruction (MPFL‐R), and to furthermore report the surgical techniques available for MPFL revision surgery. MethodsFour databases [PubMed, Ovid (MEDLINE), Cochrane Database, and EMBASE] were searched until September 29, 2020 for human studies pertaining to revision MPFL. Two reviewers screened the literature independently and in duplicate. Methodological quality of the included studies was assessed using the Methodological Index for Non‐Randomized Studies (MINORS) criteria, or the CAse REport guidelines (CARE), where appropriate. ResultsFourteen studies (one level II, one level III, two level IV, ten level V) were identified. This search resulted in a total of 76 patients with a mean age (range) of 22 (14–39) years. The patients were 75% female with a mean (range) time to revision of 24.1 (1–60) months and mean (range) follow‐up of 36.2 (2–48) months. The most common indication for revision surgery was malpositioning of the femoral tunnel (38.1%), unaddressed trochlear dysplasia (18.4%), patellar fracture (11.8%). Femoral tunnel malposition was typically treated via revision MPFL‐R with quadriceps tendon or semitendinosus autograft and may retain the primary graft if fixation points were altered. Unaddressed trochlear dysplasia was treated with deepening trochleoplasty with or without revision MPFL‐R, and patella fracture according to the nature of the fracture pattern and bone quality. Though generally, outcomes in the revision scenario across all indications were inferior to those post‐primary procedure, overall, revision patients demonstrated positive improvements in pain and instability symptoms. Transverse patella fractures treated with debridement and filling with demineralized bone matrix if required with further fixation according to the fracture pattern. ConclusionThe most common causes of MPFL failure in literature published to date, in order of decreasing frequency, are: malposition of the femoral tunnel, unaddressed trochlear dysplasia, and patellar fracture. Although surgical techniques of revision MPFL‐R to manage these failures were varied, promising outcomes have been reported to date. Larger prospective comparative studies would be useful to clarify optimal surgical management of MPFL‐R failure at long‐term follow‐up. Level of evidenceIV.