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K.–H. Chang, A. Afzal, S. LiCalzi, M.S. Segal, D.L. Purich, M.B. Grant; Nitric Oxide (NO) and Carbon Monoxide (CO) Regulate Vasodilator–Stimulated Phosphoprotein (VASP), a Key Cytoskeletal Protein Involved in Endothelial Progenitor Cell (EPC) Migration . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1710.
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Within EPCs, we have shown that NO has a critical function in regulating the distribution of the motor protein VASP, which plays a critical role in actin–based motility. Reduced NO bioavailability alters actin polymerization, affecting EPC migration and EPC–mediated vascular repair leading to development of acellular capillaries (Diabetes 2005). CO generated from heme by heme oxygenases regulates NO and is cytoprotective. We investigated whether CO promotes cytoskeletal changes through VASP phosphorylation and redistribution.
EPC (CD34+) cells were isolated from human peripheral blood of 10 diabetic and 10 nondiabetic individuals using magnetic microbeads. Cells from each individual were treated for 15 min and 4h with CO and NO donors, tricarbonyldichlororuthenium dimer and DETA NO, respectively, permeabilized and stained with anti–phospho–VASP antibody (2.4 µg/ml). Immunohistochemistry was performed with anti–VASP antibody.
Levels of phosphorylated VASP were increased in both normal and diabetic CD34+ cells following exposure of the NO donor; however, VASP activation was greater in nondiabetics than diabetic (p<0.001). VASP was redistributed to the peripheral membrane and filipodia in response to incubation with either NO or CO donor.
The defective migratory properties of diabetic EPCs appear to result from reduced VASP phosphorylation. CO can compensate for NO in states of NO deficiency (such as diabetes) by promoting cytoskeletal changes through phosphorylation of VASP and by increasing EPC migration for proper capillary repair.
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