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Maulasri Bhatta, Joshua Jianxin Wang, Sarah Xin Zhang; Role of Endoplasmic Reticulum Stress in Angiogenic Progenitor Cells Dysfunction in a Mouse Model of Type 1 Diabetes. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy is characterized by progressive vascular degeneration partially attributed to defective vascular repair by circulating angiogenic cells (CACs). Our recent work has implicated endoplasmic reticulum (ER) stress in high glucose induced dysfunction of angiogenic progenitor cells (APCs). Herein, we investigated the role of ER stress in diabetes-related angiogenic abnormalities in vivo using a streptozotocin (STZ) model.
Bone marrow-derived progenitors (BMPCs, Lin-/c-Kit+/Sca-1+/CD34+) and APCs (Flk-1+/Sca-1+/CD34+) as well as CACs (Flk-1+/ Sca-1+/CD34+) in peripheral blood and in the retina were quantified by flow cytometry in STZ-injected C57BL/6J mice at 4, 12, 24 and 36 weeks after the onset of diabetes. ER stress markers in bone marrow-derived mononuclear cells (BMNCs) and early outgrowth cells (EOCs) were determined by real-time qPCR and western blot analysis. EOC function was determined by colony formation and migration assays.
A significant increase in BMPCs was observed at week 12 after diabetes. In contrast, bone marrow APCs showed a decrease at weeks 4 and 36 but an increase at week 12, which is in line with the change of BMPCs. The number of CACs in peripheral blood reduced at weeks 4, 12 and 24 and returned to normal level at week 36, while a reduction of CACs in the retina was observed at week 12. In BMNCs, expression of ER stress markers (GRP78, ATF4, ATF6 and XBP1s) increased at week 36 with upregulation of GRP78 at weeks 4 and 24, ATF6 at week 12 and ATF4 at week 24. Moreover, expression of IL-1β was increased at weeks 12 and 36. In bone marrow-derived EOCs, increased levels of CHOP, cleaved caspase-3 and XBP-1 were seen at week 12 after diabetes, accompanied by reduced capacity of colony formation and migration. Inhibiting ER stress by 4-phenylbutyrate (4-PBA) significantly improved the function of diabetic EOCs.
Our data demonstrate a dynamic and differential activation of ER stress signaling pathways in BMNCs and EOCs in STZ mice over 36 weeks of diabetes, correlating with aberrant changes of angiogenic progenitors in bone marrow, peripheral blood and the retina. Further, diabetes-induced EOC dysfunction can be restored by inhibition of ER stress. Thus, modulating ER stress provides a promising approach to improving angiogenic progenitor function to promote vascular repair in diabetes.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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