S100A1: A Novel and Essential Molecular Component for Postischemic Angiogenesis

Critical limb ischemia is associated with significant morbidity and mortality. Revascularization is not always feasible or successful. Consequently, in a worryingly high percentage of patients, amputation is the only option. It is hoped that a wider understanding of the molecular mechanisms underpinning limb ischemia can help develop new and truly revolutionary therapeutic strategies.Article, see p 66 In this issue of Circulation Research , Most et al1 propose the S100 protein A1 (S100A1) as a novel therapeutic target in limb ischemia. S100A1 is one of the several EF-hand type proteins, which is characterized by helix-loop-helix EF-hand calcium-binding domains and responds to variations in calcium levels with conformational changes regulating the interaction with protein targets.2 S100A1 is known to be expressed in striated muscles.3,4Here, Most et al1 show that S100A deficiency in vascular endothelial cells reduces their capacity to mount an appropriate angiogenic response.1 They have performed an in-depth mechanistic investigation after observing a dramatic reduction in S100A1 levels in muscular biopsies from critical limb ischemia patients compared with healthy controls.1 This is a successful example of reverse translational research.The team already reported that S100A1 is expressed in endothelial cells, where it promotes calcium-dependent endothelial NO synthase (eNOS) activity.5 Using a global gene knockout murine model for S100A1, they demonstrated that S100A1 deficiency results in endothelial dysfunction and impaired vascular relaxation capacity.5 The new article goes further, investigating the expressional regulation of S100A1 by hypoxia and …