S100A1: A novel and essential molecular component for postischemic angiogenesis.

C ritical 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. In this issue of Circulation Research, Most et al 1 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. 1 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 en-dothelial 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 the mechanisms linking S100A1 and eNOS function. The authors elegantly demonstrate that direct calcium dependent interaction between S100A1 and eNOS promotes NO generation in endothelial cells. In addition, S100A1 attenuates protein kinase C activity, preventing inhibitory phosphorylation at the threonine-495 eNOS site (Figure). 1 A deficiency in S100A1 seems to compromise fundamental functional characteristics of endothelial cells, including the ability to proliferate, migrate, and form capillary-like tube networks in vitro. 1 Furthermore, the authors provide evidence of the importance of S100A1 in postischemic angiogenesis by inducing limb ischemia in S100A1 knockout mice and wild-type controls. Under ischemic conditions, S100A1 deficiency additionally affects vascular endothelial growth factor sig-naling by upregulating vascular endothelial growth factor-A expression (presumably via increased hypoxia-inducible factor 1) and hastening degradation of the vascular endothelial growth factor receptor 2 (possibly via increased protein kinase C activity), thus impairing the proangiogenic potential of vas-cular endothelial growth factor-A overall. 1 The authors show that hypoxia regulates S100A1 expression in cultured endothelial cells. Here, hypoxia …