Browsing by Author "Vyas, Ruchi J."

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    Loss of Angiotensin-Converting Enzyme 2 Exacerbates Diabetic Retinopathy by Promoting Bone Marrow Dysfunction
    (Wiley, 2018-09) Duan, Yaqian; Beli, Eleni; Calzi, Sergio Li; Quigley, Judith L.; Miller, Rehae C.; Moldovan, Leni; Feng, Dongni; Salazar, Tatiana E.; Hazra, Sugata; Al-Sabah, Jude; Chalam, Kakarla V.; Trinh, Thao Le Phuong; Meroueh, Marya; Markel, Troy A.; Murray, Matthew C.; Vyas, Ruchi J.; Boulton, Michael E.; Parsons-Wingerter, Patricia; Oudit, Gavin Y.; Obukhov, Alexander G.; Grant, Maria B.; Cellular and Integrative Physiology, School of Medicine
    Angiotensin-converting enzyme 2 (ACE2) is the primary enzyme of the vasoprotective axis of the renin angiotensin system (RAS). We tested the hypothesis that loss of ACE2 would exacerbate diabetic retinopathy by promoting bone marrow dysfunction. ACE2-/y were crossed with Akita mice, a model of type 1 diabetes. When comparing the bone marrow of the ACE2-/y-Akita mice to that of Akita mice, we observed a reduction of both short-term and long-term repopulating hematopoietic stem cells, a shift of hematopoiesis towards myelopoiesis, and an impairment of lineage-c-kit+ hematopoietic stem/progenitor cell (HS/PC) migration and proliferation. Migratory and proliferative dysfunction of these cells was corrected by exposure to angiotensin-1–7 (Ang-1–7), the protective peptide generated by ACE2. Over the duration of diabetes examined, ACE2 deficiency led to progressive reduction in electrical responses assessed by electroretinography and to increases in neural infarcts observed by fundus photography. Compared to Akita mice, ACE2-/y-Akita at 9-months of diabetes showed an increased number of acellular capillaries indicative of more severe diabetic retinopathy. In diabetic and control human subjects, CD34+ cells, a key bone marrow HS/PC population, were assessed for changes in mRNA levels for MAS, the receptor for Ang-1–7. Levels were highest in CD34+ cells from diabetics without retinopathy. Higher serum Ang-1–7 levels predicted protection from development of retinopathy in diabetics. Treatment with Ang-1–7 or alamandine restored the impaired migration function of CD34+ cells from subjects with retinopathy. These data support that activation of the protective RAS within HS/PCs may represent a therapeutic strategy for prevention of diabetic retinopathy.
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    Vascular Patterning as Integrative Readout of Complex Molecular and Physiological Signaling by VESsel GENeration Analysis
    (Karger, 2021) Lagatuz, Mark; Vyas, Ruchi J.; Predovic, Marina; Lim, Shiyin; Jacobs, Nicole; Martinho, Miguel; Valizadegan, Hamed; Kao, David; Oza, Nikunj; Theriot, Corey A.; Zanello, Susana B.; Taibbi, Giovanni; Vizzeri, Gianmarco; Dupont, Mariana; Grant, Maria B.; Lindner, Daniel J.; Reinecker, Hans-Christian; Pinhas, Alexander; Chui, Toco Y.; Rosen, Richard B.; Moldovan, Nicanor; Vickerman, Mary B.; Radhakrishnan, Krishnan; Parsons-Wingerter, Patricia; Ophthalmology, School of Medicine
    The molecular signaling cascades that regulate angiogenesis and microvascular remodeling are fundamental to normal development, healthy physiology, and pathologies such as inflammation and cancer. Yet quantifying such complex, fractally branching vascular patterns remains difficult. We review application of NASA’s globally available, freely downloadable VESsel GENeration (VESGEN) Analysis software to numerous examples of 2D vascular trees, networks, and tree-network composites. Upon input of a binary vascular image, automated output includes informative vascular maps and quantification of parameters such as tortuosity, fractal dimension, vessel diameter, area, length, number, and branch point. Previous research has demonstrated that cytokines and therapeutics such as vascular endothelial growth factor, basic fibroblast growth factor (fibroblast growth factor-2), transforming growth factor-beta-1, and steroid triamcinolone acetonide specify unique “fingerprint” or “biomarker” vascular patterns that integrate dominant signaling with physiological response. In vivo experimental examples described here include vascular response to keratinocyte growth factor, a novel vessel tortuosity factor; angiogenic inhibition in humanized tumor xenografts by the anti-angiogenesis drug leronlimab; intestinal vascular inflammation with probiotic protection by Saccharomyces boulardii, and a workflow programming of vascular architecture for 3D bioprinting of regenerative tissues from 2D images. Microvascular remodeling in the human retina is described for astronaut risks in microgravity, vessel tortuosity in diabetic retinopathy, and venous occlusive disease.