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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Invest+Ophthalmol+Vis+Sci
2015 ; 56
(6
): 3441-59
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Pericyte chemomechanics and the angiogenic switch: insights into the pathogenesis
of proliferative diabetic retinopathy?
#MMPMID26030100
Durham JT
; Dulmovits BM
; Cronk SM
; Sheets AR
; Herman IM
Invest Ophthalmol Vis Sci
2015[Jun]; 56
(6
): 3441-59
PMID26030100
show ga
PURPOSE: To establish the regulatory roles that pericytes have in coordinating
retinal endothelial cell (EC) growth and angiogenic potential. METHODS: Pericytes
were derived from donor diabetic (DHuRP) or normal (NHuRP) human retinae, and
characterized using vascular markers, coculture, contraction, morphogenesis, and
proliferation assays. To investigate capillary "cross-talk," pericyte-endothelial
coculture growth, and connexin-43 (Cx43) expression assays were performed.
Paracrine effects were examined via treating EC with pericyte-derived conditioned
media (CM) in proliferation, angiogenesis, and angiocrine assays. The effects of
sphingosine 1-phosphate (S1P) were assessed using receptor antagonists. RESULTS:
The DHuRP exhibit unique proliferative and morphologic properties, reflecting
distinctive cytoskeletal and isoactin expression patterns. Unlike NHuRP, DHuRP
are unable to sustain EC growth arrest in coculture and display reduced Cx43
expression. Further, CM from DHuRP (DPCM) markedly stimulates EC proliferation
and tube formation. Treatment with S1P receptor antagonists mitigates DPCM
growth-promotion in EC and S1P-mediated pericyte contraction. Angiocrine assays
on normal and diabetic pericyte secretomes reveal factors involved in angiogenic
control, inflammation, and metabolism. CONCLUSIONS: Effects from the diabetic
microenvironment appear sustainable in cell culture: pericytes derived from
diabetic donor eyes seemingly possess a "metabolic memory" in vitro, which may be
linked to original donor health status. Diabetes- and pericyte-dependent effects
on EC growth and angiogenesis may reflect alterations in bioactive lipid,
angiocrine, and chemomechanical signaling. Altogether, our results suggest that
diabetes alters pericyte contractile phenotype and cytoskeletal signaling, which
ultimately may serve as a key, initiating event required for retinal endothelial
reproliferation, angiogenic activation, and the pathological neovascularization
accompanying proliferative diabetic retinopathy.