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Ira M Herman; Pericyte Chemo-Mechanics: Regulation of Microvascular Endothelial Growth and Pathological Angiogenesis During Diabetes and Aging?. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4289.
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© ARVO (1962-2015); The Authors (2016-present)
To establish the roles that pericytes play in regulating microvascular endothelial cell growth dynamics (EC) and angiogenic activity during diabetes and aging.
Pericytes were derived from donor diabetic (DHuRP) or normal human retinae (NHuRP) and characterized using several vascular cell- and cytoskeletal-specific markers. To quantitatively assess growth state, differentiated phenotype, angiogenic potential, and cytoskeletal effector functions, microvascular cells were cultured alone, or together, to understand whether or what extent, pericytes derived from normal or diabetic donor eyes modulate endothelial growth and angiogenic activation while in co-culture. Force-generation, angiocrine, bioactive lipid, endothelial growth and morphogenesis assays were performed to evaluate capillary pericyte chemo-mechanics and microvascular cellular 'cross-talk'.
DHuRP exhibit unique proliferative and morphologic properties when compared to NHuRP, which reflect distinctive cytoskeletal and contractile protein isoform expression patterns/arrays. In contrast to NHuRP, DHuRP are unable to sustain contact-dependent or contact-independent endothelial growth arrest while in co-culture. DHuRP angiocrine effectors and Cx43 expression are markedly altered when compared to NHuRP. Aligned with results derived from angiocrine and bioactive lipid receptor antagonist assays, media derived from DHuRP markedly stimulates REC proliferation and tube formation when compared to NHuRP CM. Additionally, treatment with S1P receptor antagonists mitigates DHuRP CM growth-promoting effects on REC and S1P-mediated pericyte contraction.
Herein, we report that DHuRP significantly induce retinal endothelial growth and angiogenesis despite cell-cell contact. Further, diabetes-induced and pericyte-driven alterations in bioactive lipid, angiocrine and chemo-mechanical signaling is sustainable in vitro as pericytes derived from diabetic donors eyes seemingly possess a 'metabolic memory'. All together, our results suggest that diabetes alters pericyte contractile phenotype and cytoskeletal signaling, which may serve as a key, initiating event required for retinal endothelial re-proliferation, angiogenic activation and the pathological neovascularization that accompanies proliferative DR.
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