Abstract
BackgroundCritical limb ischemia (CLI) is characterized by lower extremity artery obstruction and a largely unexplained impaired ischemic neovascularization response. Bone marrow (BM) derived endothelial progenitor cells (EPC) contribute to neovascularization. We hypothesize that reduced levels and function of circulating progenitor cells and alterations in the BM contribute to impaired neovascularization in CLI.MethodsLevels of primitive (CD34+ and CD133+) progenitors and CD34+KDR+ EPC were analyzed using flow cytometry in blood and BM from 101 CLI patients in the JUVENTAS-trial (NCT00371371) and healthy controls. Blood levels of markers for endothelial injury (sE-selectin, sICAM-1, sVCAM-1, and thrombomodulin), and progenitor cell mobilizing and inflammatory factors were assessed by conventional and multiplex ELISA. BM levels and activity of the EPC mobilizing protease MMP-9 were assessed by ELISA and zymography. Circulating angiogenic cells (CAC) were cultured and their paracrine function was assessed.ResultsEndothelial injury markers were higher in CLI (P<0.01). CLI patients had higher levels of VEGF, SDF-1α, SCF, G-CSF (P<0.05) and of IL-6, IL-8 and IP-10 (P<0.05). Circulating EPC and BM CD34+ cells (P<0.05), lymphocytic expression of CXCR4 and CD26 in BM (P<0.05), and BM levels and activity of MMP-9 (P<0.01) were lower in CLI. Multivariate regression analysis showed an inverse association between IL-6 and BM CD34+ cell levels (P = 0.007). CAC from CLI patients had reduced paracrine function (P<0.0001).ConclusionCLI patients have reduced levels of circulating EPC, despite profound endothelial injury and an EPC mobilizing response. Moreover, CLI patients have lower BM CD34+-cell levels, which were inversely associated with the inflammatory marker IL-6, and lower BM MMP-9 levels and activity. The results of this study suggest that inflammation-induced BM exhaustion and a disturbed progenitor cell mobilization response due to reduced levels and activity of MMP-9 in the BM and alterations in the SDF-1α/CXCR4 interaction contribute to the attenuated neovascularization in CLI patients.
Highlights
Critical limb ischemia (CLI) is a major health care problem, associated with a high risk of limb loss [1] as well as a high shortterm cardiovascular ischemic event rate and increased mortality [2,3,4]
In 101 CLI patients participating in an ongoing trial [24] on the effects of Bone marrow (BM) mononuclear cell (MNC) administration, we investigated the numbers of hematopoietic and endothelial progenitor cells in BM and peripheral blood (PB), as well as Circulating angiogenic cells (CAC) outgrowth from PB-MNC and their paracrine function, in comparison to healthy controls
Levels of markers for vascular endothelial activation or injury, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin and thrombomodulin, were significantly higher in CLI patients compared to healthy controls (Table 2)
Summary
Critical limb ischemia (CLI) is a major health care problem, associated with a high risk of limb loss [1] as well as a high shortterm cardiovascular ischemic event rate and increased mortality [2,3,4]. CLI is caused by obstruction of lower extremity arteries – most often due to atherosclerosis – in combination with a yet largely unexplained impaired ischemic neovascularization response. Postnatal neovascularization in response to tissue ischemia occurs by migration and proliferation of resident mature endothelial cells and involves bone marrow (BM) derived endothelial progenitor cells (EPC) [5]. Critical limb ischemia (CLI) is characterized by lower extremity artery obstruction and a largely unexplained impaired ischemic neovascularization response. Bone marrow (BM) derived endothelial progenitor cells (EPC) contribute to neovascularization.
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