Nitric Oxide Cytoskeletal–Induced Alterations Reverse the Endothelial Progenitor Cell Migratory Defect Associated With Diabetes

Segal, Mark S.; Shah, Ronak; Afzal, Aqeela; Perrault, Cécile M.; Chang, Kyung Hee; Schuler, Anna; Beem, Elaine; Shaw, Lynn C.; Calzi, Sergio Li; Harrison, Jeffrey K.; Tran‐Son‐Tay, Roger; Grant, Maria B.

doi:10.2337/diabetes.55.01.06.db05-0803

Cited by 194 publications

(96 citation statements)

References 45 publications

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“…For example, diabetic CD34+ cells do not migrate in response to VEGF and are structurally rigid. However, incubating these cells with a NO donor corrects the migration defect as well as cell deformability [97]. Pharmacological strategies that increase eNOS expression (eNOS transcription enhancers as well as angiotensin-converting enzyme, or HMG-CoA reductase inhibitors) result in significant increases in the circulating levels of vasculogenic progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms underlying the activation of eNOS

Fleming

2009

Pflugers Arch - Eur J Physiol

370

319

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Endothelial cells situated at the interface between blood and the vessel wall play a crucial role in controlling vascular tone and homeostasis, particularly in determining the expression of pro- and anti-atherosclerotic genes. Many of these effects are mediated by changes in the generation and release of the vasodilator nitric oxide (NO) in response to hemodynamic stimuli exerted on the luminal surface of endothelial cells by the streaming blood (shear stress) and the cyclic strain of the vascular wall. The endothelial NO synthase (eNOS) is activated in response to fluid shear stress and numerous agonists via cellular events such as; increased intracellular Ca(2+), interaction with substrate and co-factors, as well as adaptor and regulatory proteins, protein phosphorylation, and through shuttling between distinct sub-cellular domains. Dysregulation of these processes leads to attenuated eNOS activity and reduced NO output which is a characteristic feature of numerous patho-physiological disorders such as diabetes and atherosclerosis. This review summarizes some of the recent findings relating to the molecular events regulating eNOS activity.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanisms underlying the activation of eNOS

Fleming

2009

Pflugers Arch - Eur J Physiol

370

319

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“…This ancillary effect of DPP-4 inhibition might have potential favorable cardiovascular therapy implications [51]. Furthermore, Segal et al reported that CXCL12 is a critical chemokine as a recruiter for EPCs toward ischemic regions, allowing these cells to participate in the events of compensatory angiogenesis [52]. The CXCL12 receptor, CXCR4, is expressed on developing blood vessels as well as on cluster of differentiation (CD)34 expressing EPCs, so that pico-and nanomolar concentrations of CXCL12 differentially influence neovascularization, inducing CD34 + cell migration and EPC tube formation.…”

Section: Status Of Cxcl12 In T2dmentioning

confidence: 99%

“…Overall, the findings of Segal et al may support a common downstream cytoskeletal alteration in diabetic CD34 + cells that is independent of the activation of growth factor receptor and, importantly, is correctable by exogenous NO. This inability of diabetic EPCs to respond to the CXCL12 may contribute to aberrant tissue vascularization and endothelial repair in diabetic patients [52]. Loader et al reported significantly higher plasma CXCL12 concentrations in T2D patients (who also presented with higher pure-tone audiometry thresholds) compared to nondiabetic subjects [53].…”

Section: Status Of Cxcl12 In T2dmentioning

confidence: 99%

Significance of CXCL12 in Type 2 Diabetes Mellitus and Its Associated Complications

Karimabad

Hassanshahi

2014

Inflammation

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Immune responses are extensively accepted as primitive etiological leading causes involved in immune system diseases. It is now well established that chemokines as the main arms of the immune system play critical roles in the regulation of immune responses in the pathogenesis of different diseases. Several environmental and genetic elements of the immune system are also believed to potentially affect both the onsets of immunological diseases. The stromal cell-derived factor-1 alpha (SDF-1α) which in new nomenclature is nominated as C-X-C motif ligand 12 (CXCL12) is involved in the development and progression of immune responses. The CXCL12 is an extensively active chemokine that serves as a recruiter for migration and trafficking of leukocytes and hematopoietic progenitor cells. Patients suffering type 2 diabetes (T2D) that ascribe heterozygous SDF-1 3'A genotype (801G/A in the 3' untranslated region) have increased insulin-dependent mobilization of adult progenitor cells, which are known to participate in angiogenesis and vascular repair. Conversely, homing of progenitor cells contributes to the diabetes vascular complications. Because carriers of the SDF-1 3'A genotype show increased levels of the CXCL12 messenger RNA (mRNA) in their peripheral blood mononuclear cells. Genetic variations of CXCL12 gene might affect trafficking of inflammatory cells or defected precursors and hence induced tendency to diabetic complications. The SDF-1 3'A genetic variation of CXCL12 influences the development of late vascular diabetic complications, and previous studies reported that this genetic variation regulates the expression of CXCL12. Therefore, the main goal of the present study was to collect the most recent reports regarding the relation between serum concentrations and SDF-1 3'A genetic variation of CXCL12 in T2D.

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“…Reducing ROS formation by inducing overexpression of manganese superoxide dismutase normalized chemokine expression and restored the defective neovasularization capacity. Also the migration deficit of CD34+ progenitor cells, isolated from diabetic patients, could be reversed by exogenous NO supplementation with an NO donor (diethylenetriamine nitric oxide (DETA/NO)) [53]. Thum et al [54] pointed out that eNOS uncoupling could be the mechanism underlying the increased ROS generation in diabetic conditions, leading to a reduced function and number of EPCs.…”

Section: Diabetesmentioning

confidence: 99%