Abstract 19266: Renin-Angiotensin Axis in Hematopoietic Stem/Progenitor Cells Predicts Vascular Dysfunction and Diabetic Retinopathy
Introduction: The renin-angiotensin system (RAS) axis plays a key role in diabetic complications and the protective role of angiotensin converting enzyme 2 (ACE2) is mediated by angiotensin 1-7 (Ang 1-7).
Hypothesis: We hypothesize that vascular remodeling in diabetic retinopathy (DR) would be associated with impaired function of hematopoietic stem/progenitor cells (HS/PC) and with a loss of ACE2 function that could be rescued by Ang 1-7.
Methods: Controls (n=13) or diabetics (n=35) with either no DR or with DR were recruited. CD34+ cells were isolated from subjects and reparative function evaluated using assays of migration (towards CXCL12) and proliferation (BrdU assay). Vascular reactivity and endothelial function were assessed in mounted aortic arches in diabetic ACE2 knockout (KO)/C57BL/6-Ins2(Akita) mice and compared to those in wildtype and diabetic Akita mice. Linage-c-kit+ (LC) cell proliferation and migration was assayed in these mice.
Results: ACE2 gene expression in CD34+ cells from diabetics without DR was increased compared to controls and diabetics with DR (p=0.0437). Mas receptor mRNA was increased in diabetics without DR, while it was reduced in DR compared to controls (p=0.0002). Presence of DR was associated with CD34+ cell migratory/proliferative dysfunction. When CD34+ cell from DR subjects were pretreated with Ang 1-7, migratory ability to CXCL12 was restored (p=0.0008). Fluorescein angiography was used to delineate retinal vasculature. Vessel generation analysis software showed an increase in small vessel density in DR subjects when compared with controls suggestive of active retinal remodeling. In Akita mice, reduced proliferative function of LC cells was linked with impaired endothelium-dependent relaxation and increased sensitivity to catecholamines of aortic arches compared to controls. LC cells from ACE2KO/Akita mice showed impairment of proliferation at as early as 3 months of diabetes (p=0.0019), which was restored by Ang 1-7 (p=0.0306).
Conclusions: Retinopathy and adverse vascular remodeling in subjects with diabetes correlated with a loss of the protective arm of RAS in CD34+cells. Loss of ACE2 exacerbates vascular dysfunction in diabetic mice. Ang 1-7 treatment was protective in HS/PC from both species.
Author Disclosures: Y. Duan: None. R.C. Miller: None. L. Moldovan: None. E. Beli: None. T. Salazar: None. S. Li Calzi: None. S. Hazra: None. J. Al-Sabah: None. M. Meroueh: None. K.V. Chalam: None. S. Raghunandan: None. R.J. Vyas: None. P. Parsons-Wingerter: None. G.Y. Oudit: None. A.G. Obukhov: None. M.B. Grant: None.
- © 2016 by American Heart Association, Inc.