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Maulasri Bhatta, Jacey Hongjie Ma, Joshua Jianxin Wang, Sarah Xin Zhang; Enhanced Endoplasmic Reticulum Stress in Bone Marrow Angiogenic Progenitor Cells in Long-term Experimental Type 2 Diabetes. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4270.
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© ARVO (1962-2015); The Authors (2016-present)
Bone marrow progenitor cells and circulating angiogenic cells (CACs) play an important role in vascular repair. In diabetes, the function of CACs is compromised contributing to the development of diabetic retinopathy; however, the underlying mechanisms are poorly understood. Herein, we examined whether ER stress, which has been recently linked to endothelial injury, is involved in angiogenic cell dysfunction in long-term experimental type 2 diabetes.
Flow cytometric analysis was used to quantify bone marrow-derived progenitors (Lin-/ c-Kit+ Sca-1+/CD34+) and blood-derived CACs (Lin- /Sca-1+ /CD34+) in 15 month-old Leprdb (db/db) mice and in their littermate control (db/+) mice. ER stress markers in diabetic (db/db) and non-diabetic (db/+) bone-marrow progenitors, retinal vascular density and CAC recruitment to retinal vasculature were measured.
The numbers of bone-marrow progenitors and CACs were significantly reduced in db/db mice. Consistently, there are fewer progenitor cells in retinal vasculature of the same mice. Diabetes-associated pathological changes were observed, including beading of retinal blood vessels and reduced vascular density, accompanied by enhanced microglial activation and increased expression of HIF-1α and VEGF in db/db retinas. These changes were associated with increased expression of ER stress markers (GRP78, p-IRE-1α, p-eIF2α, ATF4, CHOP and XBP1s) in the retina and in bone-marrow progenitors of db/db mice.
Our data indicate that increased ER stress in diabetic bone-marrow progenitors is associated with retinal vascular damage in long-term experimental type 2 diabetes and suggest a potential role of ER stress in diabetes-induced angiogenic cell dysfunction and vascular complication.
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