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Increased SDF-1alpha But Not SDF-1beta Expression With Raised CXCR4 In Human Critical Limb Ischemia

Teik K Ho¹, Shiwen Xu², Nima Aden², Carol M Black², David J Abraham², George Hamilton¹, Daryll M Baker¹ ∙ ¹Vascular Unit, Dept of Surgery, The Royal Free and University College Medical School, London, United Kingdom; ²Centre for Rheumatology, The Royal Free and University College Medical School, London, United Kingdom

Objective: The chemokine SDF-1, also known as CXCL12, binds to CXCR4, a seven-transmembrane G protein-coupled receptor that plays a critical role in many physiological processes, including stem cell homing and angiogenesis. SDF-1 is known to have two spliced variants, SDF-1alpha and SDF-1beta, but the importance of this is largely unknown. We have recently presented that SDF-1beta has more potent angiogenic properties compared to SDF-1alpha, and there is an increased microvessels in critical limb ischemia (CLI). The objective of this study is to investigate the pathophysiological expressions of the SDF-1 variants and its cognate receptor in CLI. Methods: Skeletal muscle biopsy specimens were obtained from the lower limbs of 12 patients with CLI and 12 patients without limb ischemia (controls), with ethical committee approval. Immunohistochemistry using avidin-biotin peroxidase method was performed to localize the expressions of SDF-1 variants and CXCR4. Double immunoflourescence labelling was used to colocalise cell specific antigens by confocal microscopy. SDF-1 variants and CXCR4 protein expressions were evaluated by Western blotting. Statistical analyses used Mann-Whitney U test. Results: In CLI, SDF-1alpha is extensively expressed by skeletal muscle fibres but there was minimal expression of SDF-1beta. CXCR4 is extensively expressed and is colocalised to microvessels. A significant 2.6-fold increased protein expression (p<0.05) of SDF-1alpha was noted in the CLI group. There was no significant difference in the protein expressions of SDF-1beta in both groups. CXCR4 expressions showed a 3.5-fold increase of protein expression in CLI group. Conclusions: SDF-1alpha expression is localized to muscle fibres only and is raised in CLI. However, there was minimal expression of SDF-1beta, either in muscle fibers or microvessels. The lack of SDF-1beta may partly explain the inadequate angiogenic response in CLI. The elevated CXCR4 is possibly associated with the increased microvessels.