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Pericyte Bridges in Homeostasis and Hyperglycemia

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posted on 14.05.2020 by Ada Admin, Bruce A. Corliss, H. Clifton Ray, Richard W. Doty, Corbin Mathews, Natasha Sheybani, Kathleen Fitzgerald, Remi Prince, Molly Kelly-Goss, Walter L. Murfee, John Chappell, Gary Owens, Paul A. Yates, Shayn M. Peirce
Diabetic retinopathy is a potentially blinding eye disease that threatens the vision of a ninth of diabetic patients. Progression of the disease has long been attributed to an initial dropout of pericytes that enwrap the retinal microvasculature. Revealed through retinal vascular digests, a subsequent increase in basement membrane bridges is observed. Using cell-specific markers, we demonstrate that pericytes rather than endothelial cells colocalize with these bridges. We show that the density of bridges transiently increases with elevation of Ang-2, PDGF-BB, and blood sugar, is rapidly reversed on a time scale of days, and often associated with a pericyte cell body located off-vessel. Cell-specific knockout of KLF4 in pericytes fully replicates this phenotype. In vivo imaging of limbal vessels demonstrates pericyte migration off-vessel, with rapid pericyte filopodial-like process formation between adjacent vessels. Accounting for off-vessel and on-vessel pericytes, we observe no pericyte loss relative to non-diabetic control retina. These findings reveal the possibility that pericyte perturbations in location and process formation may play a role in the development of pathological vascular remodeling in diabetic retinopathy.

Funding

NIH R21 EY028868-01, NIH-U01AR069393, NIH-U01HL127654, The Hartwell Foundation, The Stanford Allen Discovery Center (to S.M.P.).

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