Vascular complications are a leading cause of mortality and morbidity in diabetic individuals. Despite recent advances using pharmacotherapy, a cure for diabetic microvascular complications (MVC) has yet to be realized. A conceptual and technical breakthrough is imperative to identify novel targets, and a strategy to cure these complications is paramount. We believe that our provocative preliminary data coupled with recent evidence of a potential role of endothelial progenitor cells (EPCs) in vascular repair and the discovery of the vasoprotective axis of the renin-angiotensin-system (RAS) offer such a breakthrough. The protective axis of the RAS involves the angiotensin converting enzyme 2 (ACE2) which is present in both endothelial cells and EPCs and generates angiotensin-(1-7) which acting through the Mas, attenuates the vasoconstrictive, proliferative, fibrotic and hypertrophic effects of angiotensin II, the key member of the deleterious axis of RAS. In this proposal we utilize retinopathy as the MVC to test our hypothesis that the ACE/ACE2 balance within EPCs dictates their reparative capability and can therefore predict progression of retinal MVC. If MVC are already present, then genetically modifying EPCs utilizing AAV technology to increase endogenous levels of ACE2 will enhance their reparative function and reverse MVC. We put forth the following Specific Aims to test our hypothesis:
Aim 1 : Investigate whether the ACE/ACE2 imbalance within EPCs will predict progression of MVC.
Aim 2 : Test the hypothesis if the absence of ACE2 in the systemic vasculature will accelerate progression while overexpression will prevent development and progression retinovascular complications.
Aim 3 : Investigate the hypothesis that increased ACE2/Ang-(1-7) expression within the retina will stimulate mobilization, homing and reparative potential of EPCs. This integrative and multidimensional proposal is extremely innovative both conceptually and technically because it will: (i) provide evidence for our hypothesis;(ii) establish the mechanism by which the activation of the ACE2/Ang-(1-7)-Mas receptor axis within EPCs sustains cellular reparative function in diabetes;(iii) determine whether the state of the RAS in EPCs can predict the progression of retinopathy;(iv) use the highly innovative VESsel GENeration (VESGEN) technology to delineate vascular remodeling in the retina and (iv) put us in an outstanding position to transition into the clinical arena using cells that have their protective RAS axis activated, either genetically or pharmacologically, for treatment of diabetic retinopathy

Public Health Relevance

The focus of our proposal is to investigate if the balance of vasoprotective axis vs. vasodeleterious axis of the RAS within EPCs can predict progression of MVC in diabetes. Furthermore we will study if correction of this imbalance in the EPCs of diabetic patients would prevent the progression/attenuation of MVC. Outcome of these experiments will be a significant advancement in the use of ACE/ACE2 ratio as a predictor of diabetic patients and development of novel stem cell-based therapy to prevent MVC, single most important cause of diabetes-linked mortality and morbidity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL110170-02
Application #
8325567
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Reid, Diane M
Project Start
2011-09-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$445,394
Indirect Cost
$98,915
Name
University of Florida
Department
Pharmacology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Shaw, Lynn Calvin; Li Calzi, Sergio; Li, Nan et al. (2018) Enteral Arg-Gln Dipeptide Administration Increases Retinal Docosahexaenoic Acid and Neuroprotectin D1 in a Murine Model of Retinopathy of Prematurity. Invest Ophthalmol Vis Sci 59:858-869
Yan, Yuanqing; Gao, Ruli; Trinh, Thao L P et al. (2017) Immunodeficiency in Pancreatic Adenocarcinoma with Diabetes Revealed by Comparative Genomics. Clin Cancer Res 23:6363-6373
Caballero, Sergio; Kent, David L; Sengupta, Nilanjana et al. (2017) Bone Marrow-Derived Cell Recruitment to the Neurosensory Retina and Retinal Pigment Epithelial Cell Layer Following Subthreshold Retinal Phototherapy. Invest Ophthalmol Vis Sci 58:5164-5176
Bhatwadekar, Ashay D; Duan, Yaqian; Korah, Maria et al. (2017) Hematopoietic stem/progenitor involvement in retinal microvascular repair during diabetes: Implications for bone marrow rejuvenation. Vision Res 139:211-220
Basavarajappa, Halesha D; Sulaiman, Rania S; Qi, Xiaoping et al. (2017) Ferrochelatase is a therapeutic target for ocular neovascularization. EMBO Mol Med 9:786-801
Salazar, Tatiana E; Richardson, Matthew R; Beli, Eleni et al. (2017) Electroacupuncture Promotes Central Nervous System-Dependent Release of Mesenchymal Stem Cells. Stem Cells 35:1303-1315
Li, Wennan; Chen, Xingjuan; Riley, Ashley M et al. (2017) Long-term spironolactone treatment reduces coronary TRPC expression, vasoconstriction, and atherosclerosis in metabolic syndrome pigs. Basic Res Cardiol 112:54
Beli, Eleni; Dominguez 2nd, James M; Hu, Ping et al. (2016) CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes. J Mol Med (Berl) 94:1255-1265
Dominguez 2nd, James M; Hu, Ping; Caballero, Sergio et al. (2016) Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice. Am J Pathol 186:1688-700
Thinschmidt, Jeffrey S; Colon-Perez, Luis M; Febo, Marcelo et al. (2016) Depressed basal hypothalamic neuronal activity in type-1 diabetic mice is correlated with proinflammatory secretion of HMBG1. Neurosci Lett 615:21-7

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